Note: Descriptions are shown in the official language in which they were submitted.
1.
The present invention relates to 2-oxa-bicyclic prostaglandins, to a
method for their preparation and to pharmaceutical and veterinary
compositions containing them.
The compounds of the invention are 2-oxa-bicyclic prostaglandins of
formula (I)
~1
H
-(CH2)p-R (I)
~o 1~ ~ ~ q
-
4 ~2 ~3
R`l Y-c-(cH2)n ~~~X~(cH2)n2 6
whereinR5 R~
R is a member selected from the group consisting of (a) a free or
,OR'
esterified carboxy group; ~b) -C-OR', wherein each of the R' groups,
`OR'
which are the same or different, is Cl-C6 alkyl or phenyl;
~c) -Cl-120H; (d) - CON wherein Ra and Rb are independently selected
b
from the group consisting of hydrogen~ Cl-C6 alkyl, C2-C6 alkanoyl
and phenyl; (e) a radical
~ N - N
-C ~ ¦~ ' ; f) -C--N ;
NH --N
Zl is hydrogen or halogen;
L~ is zero or an integer o l to 7;
cl is l or 2;
~ is hydrogen, hydroxy, Cl-C6 allcoxy, ar- Cl-C6-alkoxy, acyloxy;
.4
~ 2.
Y is a member selected from the group consisting o-f -C1~2CH2-, -C_C-,
H, ~ Z2 H ~ ~
C=C \ (cis) and ~ C=C (trans), wherein Z2 is hydrogen or
halogen;
one of R2 and R5 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 R2 and R5-
taken together, form an oxo group;
each of R3 and R4, which are the samc or different, may be hydrogen,
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- CH2
\
CH - CH
each 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 consisting o:E -0-, -S- and -(CH2)m-
wherein m is zero or l;
R6 is a member selected from the group consisting of
~a') hydrogen;
(b') Cl-C4 alkyl;
~cl) a C3-Cg cycloaliphatic radical, unsubstituted or substituted by
one or more substituents selected from the gr~up consisting of
Cl-C6 alky]. and Cl-C6 alkoxy;
(d') aryl, unsubstituted or substituted by one or more substituents
selected frolll the group consisting of halogen, halo-Cl-C6-alkyl,
Cl-C6 alkyl and Cl-C6 alkoxy; and
(e') a snturated or unsaturated heterocyclic ring, unsubstituted or
sul)st:i.tuted i~y onc or more substi-tuents selectccl from the group consisting
of lla1Oge11, halo-Cl-C6-alkyl, Cl-C6 alkyl and Cl-C6 alkoxy;
lu~
~3~.
~3~
providecl that:
A) R6 is not an unsubstituted C3-C7 cycloaliphatic radical when R is a
free or esterified carboxy group, Zl is hydrogen, p is 3, q is 1, Rl is
hydroxy, Y is -CH2-CH2- or trans-CH=CH-, R2 is hydrogen, R5 is hydroxy,
R3is hydrogen or Cl-C6 alkyl, R4 is hydrogen or Cl-C6 alkyl, nl is zero
or an integer of 1 to 6, n2 is zero and X is -0-;
B) R6 is not Cl-C4 alkyl when R, Zl~ p~ q, Rl, Y, R2, R3, R4, R5 and n
are as defined above under A), n2 is zero or 1-2 and X is -0-; and
C) R6 is not hydrogen or Cl-C4 alkyl when R, Zl~ p~ q, Rl, Y, R2~ R3, R4,
and R5 are as defined above under A), n2 is zero, nl is zero or 1-2 and X
is -(CH2)m - wherein m is zero or 1;
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 mixtures
of the dia.stereoisomers of the compounds of formula ~I) are included in
the scope of the present invention.
In the formulae of this specification the broken line (~`~ ) indicates that
a substituent bound to the cyclopentane ring is in the ~-configuration,
i,e. below the plane of the ring, a substituent bound to the 2-oxa-bicyclic
system is in the endo-configuration and a substituent bound to a chain is in
the S-configuration; the heavy solid line ~ ) indicates that a
substituent bound to the cyclopentane ri.ng is in the ~-configuration,
i.e. above the ~plane o:E the ring, a substituent bound to -the 2-oxa-bicyclic
systcm .is in the exo-con:Figuration and a substituent bound to a chain is
1ll thc Rrconfig-lration; the wavy line attachment ( ~ ) indicates that a
substituellt: does not possess a de:Einite stereochemical identity i e. tllat
33~2
a substituent bound to the cyclopentane ring may be both in the c~-and
in the ~-configuration, a substituent bound to the 2-oxa-~icyclic 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 th R-configuration,
In the compounds of the above formula ~l) the heterocyclic ring B is
cis-fused with the cyclopentane ring A and the two bonds indicatecl by the
dotted lines ~....) are both in the u-configuration with respect to the ring
A,
The side chain ~-linked to the cyclopentane ring A in trans-configuration
with respect to the arfused heterocyclic ring B and consequently it is an
exo substituent with respect to the 2-oxa-bicyclic system.
The carbon atom of the heterocyclic ring B bearing the side chain
~ 2)p-R bears also an hydrogen atom.
~zl
en the side chain ~v~CH~~CH2) -R is in the endo-configuration with
respect to the 2-oxa-bicyclic system, then said hydrogen atom is an exo-
substituent an~d its absolute configuration is reported as ~ while when
the chain ~t~H-(CH2)p-R is in the exo-configuration, then said hydrogen
atom is an endo-substituent and its absolute configuration is reported
as ~.
Zl
The compo~mds of tl1e invention wherein the chain ~ H-~CE12) -R is in
the exo-configuratio1l, the hydrogen atom linked to the same carbon atom
o-t the ring B having necessarily the c~-absolute configuration, are reported
as 6aE1-6,9~;o.~ide ~formula I ; q = l) and 5~E1-5~9~-o~ide ~Eormula I ; q = 2)
pros~c111oic acid clerivatives (prostaglandin numbering), while the compounds
wllcrc:in the chaill
'~3
~ v~C~1-(CH2)p R is in the endo-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 (formula I ; q = l)
and 5~H-5,9c~-oxide (formula I ; q = 2) prostanoic acid derivatives
(prostaglandin numbering).
Alternatively the 6c~H-6,9c~-oxide prostanoic acid deriatives are reported
as (2'-oxa-bicyclo [3.3,~ octan-3'-exo-yl)-alkanoic acid derivatives
the 5c~H-5,9c~-oxide prostanoic acid derivatives as (2'-oxa-bicyclo ~4.3.~
nonan-3'-exo-yl)-alkanoic acid derivatives, the 6~H-6,9ct-oxide prostanoic
acid derivatives as (2'-oxa-bicyclo ~.3.~ octan-3'-endo-yl)-alkanoic
acid derivatives and the 5~H-5,9c~-oxide prostanoic acid derivatives as
(2'-oxa-bicyclo ~.3.~ nonan-3'-endo-yl)-alkanoic acid derivatives.
The 6c~H-6,9c~-oxide and 5c~H-5,9c~-oxide prostanoic acid derivatives have a
higher chromatographic mobility (i.e. a higher Rf) and a less positive
rotatory power ~ ['~] D) than the corresponding 6~H-6,Yc~-oxide and
5~H-5,9c~-oxide derivatives.
All the above notations refer to the natural compounds; the d,l-compounds
are mixtures containing equimolar amounts of nat-compounds wilich possess
the above reported absolute stereochemistry and of ent-compounds which are
mirror-like images of the formers; in the ent-compownds 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.
[`hc alkyl, alkenyl, alkynyl, alkoxy, and alkanoyloxy groups are branched
or straight chain groups,
1~refcrably R is a ~ree, salifiec1 or esterifiec1 carboxy group,
~3~2
An ar-Cl-c6-alkoxy group is preferably benzyloxy.
An aryl group is preferably phenyl, ~-naphthyl or ,~naph~hyl.
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 viny].
A C2-C6 alkynyl radical is preferably ethynyl.
When R is an esterified carboxy group it is preferably a -COOR group
wherein R is a Cl-C12 alkyl radical, in particular methyl, ethyl, propyl
and heptyl, or a C2-C12 alkenyl radical, in particular allyl~
Preferably Zl is hydrogen.
When Zl is halogen, it is preferably chlorine or bromine.
p is preferably an integer of 1 to 3.
When Rl is acyloxy, i.t is preferably C2-C12 alkanoyloxy (in particular
C2-C6 alkanoyloxy, e.g~, acetoxy, propionyloxy) or benzoyloxy.
When Z2 is halogen, it is preterably chlorine, bromine or iodine~
Preferably R3 and R4 are independently selected from the group consisting
of hydrogen, Cl~C6 alkyl and fluorine~
nl is preferably 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-C9 cyclo-
alkyl radical e~g. cyclopentyl, cyclohexyl and cycloheptyl or a C3-C9 cyclo-
alkenyl radical, e.g. cyclopentenyl, cyclohexenyl and cycloheptenyl.
Whcn R6 :is a hcterocycli.c ring~ it may be either a heteromonocyclic ring
or a lletorobicyclic ring and contains at least one heteroatom selected from
l~
38~
the group consisting of N, S and 0,
Examples of preferred heteromonocyclic radicals are tetrahydrofuryl,
tetrahydropyranyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl and tetrahydrothienyl.
Examples of preferred heterobicyclic radicals are 2-oxa-~icyclo [3.3.0]
octyl, 2-oxa-bicyclo [3.4. oJ nonyl, 2-thia-bicyclo [3,3.0~ octyl, 2-thia-
bicyclo [3.~. oJ nonyl and their aromatic analogs.
Pharmaceutically or veterinarily acceptable salts of the compounds of for-
mu.La (I) are e,g, those with pharmaceutically and veterinarily acceptable
bases.
Pharmaceutically and veterinarily acceptable bases are either inorganic
bases such as, for example, alkaline hydroxides and alkaline-earth
hydroxides as well as alumimium and zinc hydroxides or organic bases e.g,
organic amines such as, for example, methylamine,dimethylamine, trimethyla-
mine, ethylamine, dibutylamine, N-methyl-N-hexylamine, decylamine, dodecyla-
mine, allylamine, cyclopentylamine, cyclohexylamine, benzylamine, dibenzyla-
mine, c~-phenyl-ethylamine, ~-phenyl-ethylamine, ethylenediamine, diethylene-
triamine, morpholine, piperidine, pyrrolidine, piperazine, as well.as the
alkyl derivatives of the latter four bases, mono-, di- and tri-ethanolamine,
ethyl-diethanolamine, N-methyl-ethanolamine, 2-amino-l-b11tanol, 2-amino-2-
methyl-l-propanol, N-phenyl-ethanolamine, galactamine, N-methyl-glucamine,
N-methyl-glucosamine, ephedrine, procaine, clehydroabietilamine, lysine,
arginine and other c~ or ~ amino acids,
Pre~erred salts of the invention are those of thc compounds of formula (I)
w11erein R is ~COORd wherein Rd is a pharmaceutically or veterinarily accep-
tab:Lc cat:i.on deriv:ing from one of the above mentioned bases,
Pnrti.cu:lL~r:1y preferrec1 compounc1s of the inventions are 6~1-6,9c~-oxide and
t ~ ~
~3~
5~ 5,Y~-oxide compounds of formula (I) ~Yherein R is a free carboxy gI`OUp
and ~6 is Cl-C4 alkyl, C5-C7 cycloalkyl or optionally substituted phenyl.
The pre~ixes 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:
13 -6~H-6,9~-oxide-ll~J15S dihydroxy-prost-13-ynoic acid;
1~ 13t-6~H-6,9~-oxide-11~,15S-dihydroxy-15-methyl-prost-13-enoic acid;
13 -6~11-6,9~-oxide-11~,15S-dihydroxy-15-methyl-prost-13-ynoic acid;
6~H-6,9~-oxide-11~,15S-dihydroxy-15-methyl-prostanoic acid;
}3t-6~H-6,9~-oxide-11~,15S-dihydroxy-15,20-dimethyl-prost-13-enoic acid;
13 -6~H-6,9~-oxide-11~,15S-dihydroxy-15,20-dimethyl-prost-13-ynoic acid;
6~H-6,9~-oxide-11~15S-dihydroxy-15,20-dimethyl-prostanoic acid;
13 -6~H-6,9~-oxide-11~,15S-dihydroxy-20-methyl-prost-13-ynoic acid;
13t-6~H-6,9~-oxide-15S-hydroxy-prost-13-enoic acid;
13 -6~H-6,9~-oxide-15S-hydroxy-prost-13-ynoic acid;
6~H-6,9a-oxide-15S hydroxy-prostanoic acid;
13t-6~ 6,9~-oxide-15S-hydroxy-15-methyl-pros~-13-enoic acid;
13 -6~H-6,Y~-oxide-15S-hydroxy-15-methyl-prost-13-ynoic acid;
6~il-6,9~-oxide-15S-hydroxy-15-methyl-prostanoic acid;
13t-6~11-6,9~-oxide-15S-hydroxy-15,20-dimethyl-prost-13-enoic acid;
13 -6~H-6,9~-oxide-15S-hydroxy-15,20-dimethyl-prost-13-ynoic acid;
6~ll-6,9x-oxide-15S-hydroxy-15,20-dimethyl-prostanoic acid;
13t-6~i1.6,~ -ox:ide-15S-hydroxy-20-methyl-prost-13-enoic acid;
13 -6~ll-6,9~-ox:ide-15S-hydroxy-20~methyl-prost-13-ylloic acid
1~,
6f~H-6,9~-oxide-15S-hydroxy-20-methyl-prostanoic acid;
13t-6~H-6,9~-oxide-11~,15S-dihydroxy-14-bromo-pros~-13-enoic acid;
13t-6f~H-6,9~-oxide-11~,15S~dihydroxy-14-chloro-prost-13-enoic acid;
13t-6f~H-6,9~-oxide-11~,15S-dihydroxy-14-bromo-15-methyl-prost-13-enoic acid;
13t-6~H-6,9~-oxide-11~,15S-dihydroxy-14-bromo-20-methyl-prost-13-enoic acid;
13t-6~H-6,9c~-oxide~ ,15S-dihydroxy-14-bromo-15,20-dimethyl-prost-13-cnoic
acid;
13t-6f~H-6,9~-oxide-11~,15S-dihydroxy-16-methyl-16-butoxy-20,19,18-trinor~
prost-13-enoic acid;
13t-6f~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-6f~11-6,9c~oxide-11~,15S-dihydroxy-17-cyclohexyl-20,19118-trinor-prost-
-13-enoic acid;
13t-6f~H-6,9c~.-oxide-11~,15S-dihydroxy-17-cyclohexyl-20,19,18-trinor-prost-
-13-ynoic acid;
13t-6~11-6,9~-oxide-11~,15S-dihydroxy-16-phenoxy-20,19,18,17-tetranor-13-
-enoic acid and the p-fluoro, p-chloroJ p-methoxy, o-fluDro, m-fluPro,
m-trifluoromethyl J m-chloro-phenoxy analogs thereof;
13t-6~H-6,9~-oxide-11~,15S-dihydroxy-17-(2'-tetrahydrofuryl)-20,19,18-
-trinor-prost-13-enoic acid;
13t-6~H-6,9c~-oxide-llcl,15S-dihydroxy-17-(2~-tetrahydrothienyl)-20J19,18-
-trinor-prost-13-enoic acid;
13t-6f~H-6,9~-oxide-11~,15S-d;.hyclroxy-16-benzyloxy-20,19,1S,17-tetranor-
-13-enoic acid and the p-fluoro, p-chloro, p-methoxy, o-fl~loro, m-fluoro,
nl-tri:fluoromethyl, m-chloro-benzyloxy analogs thereof;
l3t-S~H-S~9~ ox:iclcll~,:L5S-dihydroxy-prost-13-enoic acid;
5f3ll-5,~ -o~:ide-l].~,l5S~cl:illydroxy-prostalloic acid;
i~
10 .
13 -5~11-5,9~-oxide-ll~,15S-dihydroxy-prost-13-ynoic acid;
13t-5~ 5,9~-oxide-11~,15S-dihydroxy-16S-methyl-prost-13-enoic acid;
13t-5~H-5,9~-oxide-11~,15S-dihydroxy-:L6R-methyl-prost-13-enoic acid;
as well as the 5-bromo, the 5-iodo, the 5-chloro analogs of all the
6~}1-6,9~-oxide derivatives above listed, as well as the 4-bromo,
the 4-iodo, the 4-chloro analogs of all the 5~H-5,9~-oxide derivatives
above listed, as well as the 15R-epimers, the 15-oxo-derivatives and
the 6~H- and the 5~}1-diastereoisomers of all the compounds mentioned
above.
~.~
~15 3~
11 .
The compounds of the invention are prepared by a process comprising:
reacting a compound of formula (II)
Z
H
CH-(c~l2)p-R
o ~ ~(CH2)q (II)
R'l' CHO
wherein
P~ Z13 and q are as defined above, R" is (a") a free or esterified carboxy
OR'
group; (b") a group -C -OR', wherein each of the R' groups is as defined
OR'
above; (c") the group -CH2-R7, wherein R7 is hydroxy or a known protecting
group bound to the -CH2- group by an ethereal oxygen atom; (d") -CON
wherein Ra and Rb are as defined above; ~e") a radical of formula
~ N - - N
C\ 11
NH --N
(f") - C_N;
R'l is hydrogen, hydroxy, Cl-C6 alkoxy, ar-Cl-C6 alkoxy, acyloxy or a known
protecting group bound to the ring by an ethereal oxygen atom~
with a compound of formula ~III)
12 ~R3
E - C - CO - ~C~12)n - C - X - ~CH2)ll2 R6 (III)
whorc:il1 L is a group ~C6115)3P - or a gro~1p (Re0)2P-
3i 3~
12.
wherein each of the Re groups, which are the same or different, is alkyl
or aryl and Z2~ R3, R~, nl, n2, ~ and R6 are as defined above, so
obtaining, after the removal of the known protecting groups, if present,
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 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 formula (I) wherein one of R2 and R5 is hydrogen and
the other is hydroxy 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) wherein 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 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 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, 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
-Cll2CH2- or, if desired, dehydrohalogena-ting a compound o:E formula (I)
wherein Zl is hydrogen ancl Y is -Cl-l=CZ2 - wherein Z2 is halogen, to give a
compo~md o:E formula (I) wllerein Y is -C~C- and Zl is hydrogen or, if
dcsired, hydrogellatil-g a compound oE :Eormula (I) wherein R2 and R5, taken
togcthcr~ Eorm an oxo group and Y is -Cl-l=CZ2- wherein Z2 is hydrogen,
3~
13.
to give a compound of formula ~I) wherein R2 and R5, taken together,
form an oxo group and Y is -CH2CH2- or, if desired, dehydrohalogenating a
compound of formula ~I) wherein Zl is hydrogen, R2 and R5, taken together,
form an oxo group, and Y is -CH=CZ2- wherein Z2 is halogen, to give a com-
pound o:f 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, ta]cen together, form an oxo group, ~o give a com-
pound 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 together, form an oxo group, 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 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, to give a compound of for-
mula (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, C2-C6 alkynyl or aryl;
and/or, if desired, converting a compound of formula (I) into another
compound of formula (I) and/or, if desired, salifying a compound of
formula (I) to obtain a pharmaceutically or veterinarily acceptable salt
thereof and/or, if desired, obtaining a free compound of formula (I) from
a salt thereof and/or, if desired, separating a mixture of isomers into the
single isomers.
~33~
1~ .
The known protecting groups, i e , ether groups, are convertible to
hydroxy groups under mild conditions3 e.g., acid hydrolysis. Examples are
acetal ethers, enol ethers and silyl ethers.
The preferred groups are
- \ OAlk
(CH3)3-SiO- , ~ O- ~ O -
(~o, 0~ i-O-
OAlk / Cl ~
CH3 C}13 CH3
wherein W is -O- or -CH2- and Alk is a lower alkyl group.
The cycllzation reactions described in this specification such as e.g.
the herebelow described cyclization of a compound of formula ~IV) are all
identical reactions as to their mechanism and the number of the isomers
contained in the reaction mixture is the same for all the above cycliza-
tions. Thus for example the halocyclization reaction to give a compound
of formula ~II)can give to a mixture of four components, i.e. compounds
of formula (II) wherein Zl is halogen, consisting in a couple of
diastereoisomers having the side chain vvvv~H-(C1-12)p-R in the exo-
configuration and differing each other
for the S or R configuration of the halogen Zl and a couple of diastereo-
isomers having the side chain ~ (c}-l2)p-R in the endo-configuration
and differing each other :Eor the S or R configuration of the halogen Zl
While t11e chron1atograp}1ic mohility ~R~) of the endo-isomer is clearly
c1iEferent from the chromatographic mob;lity of the exo-isomer, the
20 c1iffercnce o:E RJ between two endo- ~or exo-) isomers diEfering each other
15.
only for the S or R configuration of the Zl substituent, is very small.
The couple of diastereoisomers wherein the chain ~C~I-(CI-12) -R is in
the exo-configuration may be seperated from the couple of diastereoisomers
wherein said chain is in the endo-configuration by fractional crystalliza-
tion e,g. from diethylether but preferably thin layer preparative
chromatography, by column chromatography or by high speed liquid chromatog-
raphy,
The separation by thin layer preparative chromatography or by column
chromatography is preferably carried out on a support of silica gel or
magnesium silicate with methylene chloride, diethylether, isopropylether,
ethylacetate, benzene, methyl acetate, cyclohexane or their mixtures as
elution solvents.
The reductive dehalogenation of a compound of formula (I) wherein Zl is
halogen, to give a compound o~ formula (I3~ wherein Zl is hydrogen, is
performed by reduction, e.g. with chromous acetate or a hydride such as
tri~n-butyl)tin hydride, or by catalytic hydrogenation.
I~hen it is desired to obtain a compound of formula (I) w]lerein Y is 7C--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
acetate.
i~hen it is desired to obtain a compound of formula (I) wherein R2 and R5
taken together :Eorm an oxo group, by the dehalogenation of the compound
o-E Eormula (I) wherein Zl is halogen, the reaction time should not exceed
halE an hour.
e~ e rc.luctlve clehalogenation is carried out with chromous acetate, this
~83~
16,
reagent is added? with stirring, to a cooled solutlon of the compound
of formula (I) wherein Zl is halogen, in a mixture of ethanol and aqueous
sodium or potassium hydroxide under an atmosphere of nitrogen. The reaction
mixture is then stirred one to three days at room temperature, according
to the method described in J,Am,Chem.Soc, 76, 5~99 ~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 the
compound of formula (r) wherein Zl is halogen, Suitable solvents for the
reaction are aromatic hydrocarbons such as benzene or toluene and ~he temp-
eratures preferably are between room temperature and about 70 C.
Preferably the reaction is carried out at about 55 C in benzene and lasts
about 12 hours.
The catalytic hydrogenation of a compound of formula (I) wherein Zl 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
compound~ e.g,, at 30-60 C either at atmospheric pressure or under pressureJ
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 CaCO3 and optionally in the presence
of an ammonium salt, e.g., ammonium acetate or propionate.
The reductive dehalogenation converts a compound of formula ~I) wherein Zl is
halogen into a compound of formula ~r) wherein Zl is hydrogen and therefore
during the dehalogenation the carbon atom carrying the Zl substituent loses
its asymmetry.
Tll~ n~lmbcr of the poss:ible diastereoisomers consequently contained in t!~e
aollalogellatioll reactiOtl mixt~lre is lower than the number of diastereoisomers
cont.l:inecl:in thc llalocyclization reaction mixture.
~3~
When the reductive halogenation is carried out directly on the mixture of
four diastereoisomers obtained from the halocylization process, a mixture
of two only diastereoisomers of formula (I) wherein Zl is hydrogen is
ob-tained, differing each other for the exo- or endo-configuration of the
side chain ~CH2-~CI-12) -E~-
When the reductive dehalogenation is carried out on a singlc couple of
diastereoisomers of formula (I) having the side chain ~V~CI~-(CE12~p-R,
Zl
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 formula CI~ wherein Zl is hydrogen is obtained wherein the side
chain ~v~CH2(CE-12)p-R is in the exo- or in the endo-coniiguration.
If a mixture of the above diastereoisomers is obtained the single diastereo-
isomers may be easily separated by fractional crystallization or by column
chromatography as described above ~or the separation of the diastereoisomers
whcrein Zl is halogen. g
When in the compound of formula (III) E is (R 0)2P-, wherein Re is aryl,
it is preferably phenyl; when R is alkyl, it is preferably Cl-C6 alkyl,
The reaction between an aldehyde of formula ~II) and a compound of formula
(III) is carried out with an excess of the compound of formula (III), e.g.,
at least 1.01 molar equivalent of the compound of formula (III) for each
mole oE the compound oE formula ~II)
~ny inert solvent can be used, such as linear and cyclic ethers, e.g ethyl
etller, tetrahydrofuran, d:ioxane, dimethoxyethane, aliphatic or aromat:ic
hydrocarbon~s, e.g., n-heptane, n-hexane, benzene, toluene or halogenated
llydroc~a:rbolls, e.g. methylene-chloride, tetrachloroethane and also mixtures
oE thcse solvents.
33
~3~a2
18.
The reaction temperature may vary between the freezing and the boiling
points of ~he solvent.
When the reaction is carried out with a compound of formula (III) wherein
E is (ReO)2P the preferred tempera~ure is the room temperature i,e. from
about lO~ to about 25 C, when the reaction is carried out with a compound
(~)
of formula (III) wherein E is ~C6}l5)3 P- , the pre-ferred temperature is the
reflux temperature of the solvent.
rlhe product of the reaction between a compound of formula (II) and a
compound of formula (III) is a mixture of a compound of formula (I) wherein
Y is trans-CH=CZ2- wherein Z2 is as defined above and a compound of formula
(I) wherein Y is cis-CH=CZ2- wherein Z2 is as defined above, in a ratio
varying between approximately 90:10 and 95:5.
The compound of formula (I) wherein Y is trans-CII~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 concen-tration of tile mother
liquor and subsequent chromatographic separation of the residue, either by
column or preparative 'l`LC chromatography using silica gel or magnesium
silicate as support and e.g, methylene chloride, diethylether, isopropylether,
ethylacetate, benzene, cyclohexane or their mixtures as elution solvents.
The removal of the known protecting groups bound to the ring ~r to the chain
by an ethereal oxygen atom is, whenever required, performed under conditions
of milcl 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 lllay be water, acetone, tetrahydrofuran, dimethoxyetilane or a lower
alip}lat;c nlcoho:L, or with a sulphonic acicl, e.g., p-toluensulphonic acid
in a solvent such as a lower aliphcltic alcohol, dry metllanol or dry ethanol,
~'
3~
L9.
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-building co-solvent which is
miscible with water and which can be easily removed in vacuo at the end of
the reaction.
Either 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 Z2 is as defined above and wherein 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
-CH=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 reduction of an obtained 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 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 out with alkaline or alkaline-earth
metal borohydrides, preferably sodium, lithium, calcium) magnesium or zinc
borohydride, using from 0.5 to 6 moles of the -reducing agent for each mole
of the compound oE formula (I). The recluction may be performed either in
atlueous or anhydrous inert solvents S~lCh as linear or cyclic ethers, e.g.,
ethyl et}ler, tetrallydrofurall, dimethoxyethane, clioxane or aliphatic
or aromatic hydrocarbolls, t.g., n-heptane or benzene, or halogenated
~3~
20.
hydrocarbons, e.g, methylene dichloride, or hydroxylated solvents, e.g.,
ethyl, methyl or isopropyl alcohol, or mixtures of these solvents,
The reaction temperature may vary between approximately -~0C and the
boiling point of the solvent used, but the preferred temperature ranges from
about -20C to about 25C.
~ 0~1
This reduction leads to a mixture of the two epimeric S~-C- ) and
~OH ~}1
R ~-C-" ) alcohols from which the single epimers can be separated, if
desired, by fractional crystallization, 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., with CH C12, ethyl ether, isopropyl
ether, ethyl acetate, methyl acetate, benzene, cyclohexane or mixtures of
these, or by high speed liquid chromatography.
The optional conversion of a compound of formula ~r) 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 one of R2 and R5 is hydroxy
and the other is Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl and Y is
-Cll=CZ2- wherein Z2 is as defined above, may be carried out by treatment
with a Grignard reagent of formula R"'-MgHal, wherein Hal is halogen,
preferably bromine or iodine and R'l' 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 oE the magnesium
derivative for each mole of ketone, operating in anhydrous solvents which
may be linear or cyclic ethers~ e.g., ethyl ether, tetrahydrofuran, dioxane,
clillletlloxyetllallc or aliphatic or aromatic hydrocarbons, e.g,, n-heptane,
n-hcYane, benzene, toluene, at temperatures varying from approximately -70C
to the bo:il:ing pOillt o:E the solvent used . The preferred temperatures range
~l~83~3~12
21.
between _60GC and 10C.
The optional etherification of a compound of formula (I) wherein Y is
-CH=CZ2~, wherein Z2 is as de~ined 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
defined above 9 and one of R2 and R5 is Cl-C6 alkoxy or aralkoxy and the
otheris ihydrogen, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl) may be
carri.ed out, for example, by reaction with an optionally aryl-substituted
diazoalkane in the presence of a catalyst such as flwoboric acid or boron-
trifluoride and in an organic solvent such as dichloromethane or by reactionof the free or salified hydroxy group with an alkyl or aralkyl halide in
presence of a base such as silver oxide and in a solvent such as dimethyl-
sulphoxide or dimethylformamide.
The optional hydrogenation of a compound of formula (I) wherein Y is -CH=CZ2-,
wherein Z2 is hydrogen, to give a compound of formula ~I) wherein Y is
-CH2-C~l2 is carried out, e.g., catalytically, preferab~y in an alcoholic
solvent, in the presence of platinum or palladium on charcoal as catalyst
at temperatures varying from about -40C to the reflux tempera~ure of the
solvent.
When it is desired to obtain compounds of formula (I) wherein Zl is halogen
and Y is -CH2-CH2- the hydrogenation ~s preferably carried out at tempera-
tures ranging from about -40C to about -20C.
The optional dehydrohalogenation of a compound of formula (I) wherein Zl
is llydrogen, and Y is -Cl-l=CZ2-, wherein Z2 is halogen, so as to ob-tain the
corresponding compounds of formula (I) wherein Zl is hydrogen and Y is
-C'C-, mny be ccnlrlcd out using a dehydrohalogenating agent preferably
sclectcd from tlle group of a dimetllylsulfinylcarbanion of formula Cl-13SOCH2( ),
34~
22.
diazabicycloundecene~ diaza.bicyclononene, the amide or the alkoxide of an
alkaline metal, From 1 to S, and preferably Erom 1.5 to 1.~, 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 atmosphericoxygen, in an inert solve:nt such as dimethylsulphoxideJ
dimethyformamide, hexamethylphosphoramide; a. linea.r or cyclic ether, e.g,,
dimethoxyethane, tetra.hydrofuran, dioxane; an aromatic hydrocarbon, e.g.,
benzene, toluene; or liquid ammonia or a mixture of these solvents.
The reaction temperature may vary between the liquefa.ction point of the
ammonia and approximately 100 C, but the preferred temperature is room
temperature.
Depending on the solvent, the reaction temperature and the molar ratio
used between the reagent a.nd the compound, the reaction time may vary from
a few minutes to several hours,
The optional reduction of a compound of formula CI) wherein R2 and R5 ta.ken
together form an oxo group and Y is -CH2-CH2- or -C-C- to give a compound
of formula. (I~ wherein one of R2 and R5 is hydrogen and the other is hydroxv
and Y is -CH2-CH2- 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
together form an oxo group and Y is -CH=CZ2-, wherein Z2 is as defined above,
The optiona.l conversion of 1 compo~md of formula (1) wllerein R2 ancl R5 taken
together form a.n oxo group a.nd Y is -CH2-C~I2 or -C-C- into a compound of
formula (I) wherc;.n one of R2 a.nd R5 is hydroxy and the other is Cl-C6 alkyl,
C2-C6 a.ll;cllyl, C2~C6 alkynyl or aryl may be effected under the same reaction
cond:it:i.ons clescr:ibed above for the analogous conversion of the compounds o:E
~J~
formula (I) wherein Y is -Cl-l-CZ2-. wherein Z2 is as defined above.
Also the cptional etherific.ltion of a compound of formula (I) wherein
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 he
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), the
preparation of a free compound from a salt and the separation of the isomers
from a mixture may be carried out by known methods.
A compound of formula (I) wherein R is 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
appropriate alcohol, e,g., a Cl-C12 aliphatic alcohol, in the presence of
an acid catalyst, e.g., p-toluenesulphonic acid and also by treatment with a
diazoalkane.
The opt;onal conversion of a compound of formula (I) wherein Rl is hydroxy
into a compound of formula (I) wherein Rl is acyloxy, if desired, may be
performed in a conventional manner, e.g., by treatment with an anhydride
a halide, such as a chloride of the appropriate carboxylic acid in the
presence of a base.
When one of R2 and R5 :is hydroxy, this hydroxy group may be protected before
the acylat:ion by one oE thc known protecting group mentioned above.
..~ ;.~
~ 2~
The optional conversion of a compound oE formula ~I) wherein R is an
esterified 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 op-
tional saponification may be carried out selectively with respect to the ester-
ified carboxy, if desired, by transesterification, i.e., by reacting it in tile
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 compound of formula (I) wherein Rl is Cl-C6 alkoxy or aralkoxy,
if desired, may be carried out by the usual methods of the etherification, for
example as described above for the etherification of a compound of formula (I)
wherein one of R2 and R5 is hydroxy.
When it is desired to etherify only one o several hydroxyl functions
present it is useful to protect before the etherification the hydroxy groups
which it is desired to not etherify, 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 carboxy group into a compound of formula (I) wherein R is
-C~12-0~-1, if desired, may be carried out, e. g., by reducing the ester with
LiAl~14 in ethyl ether or tetrahydrofuran at reflux temperature.
Tllc optional conversion oE a compound of :Eormula (I) wherein R is a
carboxy group into a compou1ld of formula (I) wherein R is -C0-N \ , wherein
Rb
,~,.... .
3~2
Ra and Rb are as defined above, may be performed by ~reatment with an amine of
formula NHRaRb in the presence of a condensing agent, e.g., a carbodiimide such
as dicyclohexylcarbodiimide, and the optional conversion o:E a compound of for-
mula (I) wherein R is an esterified carboxy into a compound of formula (I)
wherein R is -CON\ a may be effected by treatment with an amine of formula
Rb
NHR Rb in a suitable organic solvent at reflux temperature for 2-3 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 / ¦l , may be carried out by converting the carboxy group into the cor-
\NH-N
responding halide, preferably chloride, e.g., by reaction with thionyl chloride
or oxalyl chloride in dioxane or dichloroethane at reflux temperature, then
reacting the halide, e.g., with ammonia, to give the amide, dehydrating the
amide to nitrile, e.g., with p-toluenesulphonylchloride in pyridine at approx-
imately 90 C-100 C" and finally reacting the nitrile with sodium azide and
ammonium chloride in dimethylformamide at a temperature varying between the
room temperature and 100 C. But preferably the hereabove reported conversions
/ N -N
of the carboxy group into -CN or -C / ¦ ¦ are performed on the starting materi-
~NH-N
als i.e. for example on the compound of formula (II).
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 tlle geometrical isomers from their mixtures may bc effected by conven-
tional methods.
. g~
~33~
The compound of formula (II) wherein Zl is halogen may
be prepared by halocycli.zation of a compound of formula (IV)
OH ~(CH2)q~D-(CH2)p-R"
(~ I (IV)
Ri G
wherein R", p, q, D and Ri are as defined above and G is a pro-
tected aldehydic group or a protected -CH20H group, preferably a
/ORlo
member selected from the group consisting of -CH or
~ SRl o ~ ORl o
-CH \ wherein Rlo is Cl-C6 alkyl;
A
- 26 -
~3~
\ ~S 27.
2)n3 Cll\ ~(C~12~n wherein n3 is a.n integer of 2 to ~,
2 3; CH --CH2-c6H5 or -Cll2--cll2 3
of the protecting groups and by the selective oxida.tion of -CH20H, when
obtained, to -Cl10.
The halocyclization of a compound of formula ~IV) may be performed by reac-
tion with either a stoichiometric amount of a small excess of a halogenating
agent in an inert solvent, in either the presence or in absence of a base,
Preferred halogenating agents are, e.g., iodine, bromine, chlorine, bromodiox-
ane, bromopyridine, Br2.pyridine~HBr~ KI3, pyrroli.done-hydrotribromide, an
N-ha.loamide such as N-chloro-succinimide, N-bromo-succinimide, N-iodo-suc-
cinimide, a cupric halide such as CuC12 or CuBr2, a mixed halide such as
ICl or IBr, as well as a mixture ot an alkaline chloride with an allcaline
chlorate, a mixture of an alkaline bromide with an alkaline bromate or a
mixture of an alkaline iodide wi.th an a.lkaline broma.te.
Suitable solvents are, for example, halogenated hydrocarbons such as CHC13,
CCl~, Cl-12C12; aliphatic hydrocarbons such as n-hexa.ne, n-heptane; cycloali~
phatic hydrocarbons such a.s cyclohexane; aromatic hydrocarbons such as
benzene, toluene, pyridine, cyclic or linear ethers~ e.g., dioxane, tetra-
hydrofuran, diethylether, dimethoxyethane; as well as mixtures thereof.
2n Preferred solven-ts are halogentaed hydrocarbons, e.g. C}-12C12, since both
the compound of formula ~IV) and the ha.logenating agent are usual]y
soluble in these solvents.
st~ichlometric amount of a ba.se is necessa.ry when a hydrohalic ac:id is formed
during the hcl.locyclization reaction.
Such a ba.se may be a.n inorga.nic ba.se~ e,g., an a.lkaline or an alkaline-
carth oxide, carbona.te or bicarbonate, e.g., CaO, CaC03 and K2C03, NallC03,
Na2C03; a.rl orga.nic basc such as a tertia.ry a.mine~ e.g., triethylamine; or an
~3~
28.
aromatic base, e.g., pyridine or an alkyl-substituted pyridine; or an
anionic ion-exchange resin.
The halocyclization reaction is preferably carried out at temperatures
ranging from about -70C to about 100G; preferably the reaction is perf`ormed
at room temperature.
The reaction times range from few minutes to several days, but usually do
not exceed two hours and often a few minutes are sufficient to complete the
reaction.
The removal of the protecting group from the aldehydic or alcoholic functions
may be carried out by mild acid hydrolysis in the same conditions already
described in this specification for the removel of the protecting groups
(i.e. ether groups) of the hydroxylic functions.
The selective oxidation of -CH20H to -Cl10 may be effected in a conventional
manner, e.g. by treatment with an excess of at least 3 moles per mole of
primary alcohol of dicyclohexylcarbodiimide in benzene-dimethylsulphoxide
and in the presence of an acid catalyst, e.g., pyridine trifluoroacetate or
phosphoric acid.
The compound of formula (II) wherein Zl is hydrogen may be prepared either
by the dehalogenation of a compound of formula ~II) wherein Zl is halogen
according to the method reported above for the conversion of a compound of
formula ~I) wherein Zl is halogen into a compound of formula ~I) wherein
Zl is hydrogen or by a process comprising the cyclization of a compound of
formula (IV) in the presence of a source of Hg( )ions and the subsequent
reduction oE the obtained compound.
" ....
29
Suitable sources of Hg( ) ions for the cycliæation of the compound
of formula IV 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 l.Ol to 1.5,
preferably 1.2, equivalents of the mercuric compound for each mole of the
compound of formula (IV), 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 0C 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
(II) 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 mixture, which may be
carried out according to known methods, e.g., those already described above,
may be effected at this point, if des-red.
The reduction of the compound obtained by cyclization of the compound
of formula IV may be carried out by treatment with mixed hydrides such as
alkaline, e.g., sodium, potassium or lithium borohydrides, with alkaline-earth,
e.g., calcium or magnesium, borohydrides in an inert solvent, preferably a
solvent miscible with 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 benzene; or also by treatment with hydrazine
hydrate in a lower aliphatic alcohol, e.g., methanol or ethanol as solvent, at
temperatures varying from room temperature to the reflux temperature of the
solvent used. O
Tlle compound of formula (III) wherein E is (R 0)2P - may be prepared
by treatment of a phosphonate of Eormula (V)
R O ~ 12 ~R3
e ~ p - C - CO - (CH2)n - ~ - X (C 2 n2 6 (V)
e H R4
wherein R ~ Z2~ nl, R3, R4, X, n2 and R6 are as defined above, with at least an
equivalent of a base preferably selected from the group consisting of an
alkaline or alkaline-earth hydride, e.g., sodium, potassium, lithium or
calcium hydride; an alkaline alkoxide, e.g., sodium or potassium tert.butoxide;
an alkaline or alkaline-earth metal amide, e.g., sodium amide; an alkaline or
alkaline-earth derivative of a carboxy-amide, e.g., sodium acetamide or sodium
succinimide.
(+)
The compound of formula III wherein E is (C6H5)3 P- may be prepared by
reacting a compound of formula (VI)
12 ~R3
Hal-C-CO-(cH2)n ~~C~X~(CH2)n2 6 (VI)
H R4
wherein
~2' nl, R3, R4, X, n2, R6 are as defined above and Hal is a halogen atom, with
1-1.2 molar equivalent of triphenylphosphine in an inert organic solvent such
as e.g. benzene, acetonitrile, diethylether, then treating the triphenyl-
phosphonium halide so obtained with an equivalent amount of an inorganic base such
as, for example NaOH, KOH, Na2CO3, NaHCO3.
The compound of formula (IV) may be prepared, e.g., according to
Tetrahedron l.etters No. 42, 4307-4310 (1972).
The compound oE Eormula (V) wherein Z2 is halogen may be obtained
by halogenating a compound of formula (V) wherein Z2 is hydrogen in a conventional
manner~ operating substantially as in the halogenation of ~-ketoesters.
The compollnds of formula (V) wherein Z2 is hydrogen may be prepared
,. ~ j~.i
31.
by known methods, e.g. according to E.J. Corey et al, J. Am. Chem. Soc. 90, 3247
(1968) and E.J. Corey and G.K. Kwiatkowsky~ J.Am. Chem. Soc., 88 5654 (1966).
The compounds of formula VI are kno~n compounds or may be prepared
by known methods.
The compounds of the invention can be used, in general, for the same
therapeutic indications as the natural prostaglandins in either human or
veterinary medicine.
In particular, those having an acetylene bond in the 13,14-position
instead of an ethylene and those with mono and di-substituuents 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
~hether the compounds of the invention possess PG-like or thromboxane ~TXA2)-
li.ke or PGX-like activity, they were at first tested by a superfusion cascade
technique by the method of Piper and Vanel Nature 223, 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~ug/ml) is also added to prevent -the endogenous
biosynthesis of prostaglandins.
Contraction of rat colon ~RC), rat stomach strip ~RSS) and bovine
coronary artery~BCA), and relaxation of rabbit mesentery artery ~Rb~lA) are
assumed to represent prostaglandin-like cativity. TXA2-like activity is
indicated by RbMA is contracted and must be confirmed by in vitro platelet
pro-aggregation activity, since PGF2 -like compounds also contract RbMA, as
opposed to PGE. Finally, PGX-like activity is inclicated by the relaxation of
BCA, and is confir~ned by in vitro platelet anti-aggregation activity.
Synt}letic PG~2 and both the biosynthetic TXA2 and PGX are utilized
as stan-larcl compoullds.
:~L83~2~ 32
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 ethanol
just before testing; the stock 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-63 H-6,9~ -oxide-prostenoic
acid was taken as the parent compound ancl is called 6~ H-6,9~ -oxide; the
diastereoisomer 13-trans~ ,15S-dihydroxy-6 ~H-6,9~ -oxide-prostenoic acid
is then referred to as 6~ H-6,9 ~-oxide. The chemical names of the other tested
compounds arealso referred to those of the parent compounds. The compounds were
tested at concentrations up to 100 mg/ml.
The results obtained showed that, in general, the 6~ H-diastereoisomers,
e.g., the compounds 6~ H-6,9~ -oxide, dl-6~ H-5-bromo-6,9Cl-oxide, 6~ H-6,9~ -
oxide-16-m-CF3-phenoxy- ~-tetranor and 6~ H-6,9~ -oxide-16-m-chloro-phenoxy- ~-
tetranor possess BCA-relaxing activity and therefore have PGX-like activity.
Among the 6~ H-derivatives, only the compound dl-6~ H-6,9~-oxide-16-
methyl-16-butoxy-~ -tetranor (also named 13-trans-6~H-6(9 ~)oxide-llct,15S-
dihyroxy-16-methyl-16-butoxy-18,19,20-trinor prostenoic acid) showed a BCA-
contracting activity. The 6ct H-derivatives, e.g. the compound 6~ H-6,9Ci-oxide,dl-6ct H-5-bromo-6,9~ -oxide, dl-6 ~H-6,9~ -oxide-16 methyl-16-butoxy-~ -
tetranor (also named 13-trans-6ct H-6(9~ )oxide-ll~ ,15S-dihydroxy-16-methyl-16-butoxy-18,19,20-trinor prostenoic acid), 6~ H-6,9~ -oxide-16-m-CF3-phenoxy-~ -
tetranor and 6~ H-6,9~ -oxide-16-m-chloro-phenoxy- ~-tetranor also showed BCA-
contracting activity.
In general, the exo-configuration is associated with ~CA contraction.
Furtherlllore, the compounds of the invention have hypotensive activity in
mammals as does the natural compound PGX. ~lowever~ as compared to PGX, they
have the great advantclge o;~ a higher chemical stability and can be used in
~ 3~ 33
pharmaceutical formulations.
The hypotensive activity was demonstrated by 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 6c~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 6a H). Moreover,
the systemic pressure, both systolic and diastolic, was depressed from 0.05
ug/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 vasculature and, therefore in the prevention and treatment of
diseases such as phlebitis, hepato-renal syndrome 3 ductus arteriosus, non-
obstructive mesenteric ischemia, arteritis and ischemic ulcerations of the leg.
Among the compounds of the invention, in particular, the 6~ H-
derivatives 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-6,9Cl-oxide-16-_-
CF3-phenoxy- ~-tetranor, dl-6~H-6,9t~-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.~.,
Nature (London) 194, 927 (1962)] there is evidence that the compounds 6~H-6,~-
oxide, dl-6~tl-5-bromo-6,9c~-oxide, 6~H-6,9~-oxide-16-_-CF3-phenoxy-~ -tetranor
~nd 6~tl-6,9c~-oxicle-16-m-chloro-phenoxy-~ -tetranor mimic the biosynthetic PGX in
its platelet-antiaggregating properties.
Tlle compounds investigated were incubated ~Eor 2-3 minutes at 37C in
thc PRP prior to tlle addition oE the aggregating agents, arachidonic acid
!~
~33~
3~1
(0.~l mM), ADP (lO~iM), collagen (38 ~M) or adrenaline (15 ~iM). The potency ratio
for the compound is, e.g., 1:10 for arachidonic acid-induced aggregation flnd
1:100 for ADP-induced aggregation, as compared with biosynthetic PGX.
A very interesting increase in the anti-aggregating potency follows
20-methyl substitution in both the 6~H- and 6~H-6,9~-oxide parent compounds.
Similarly, 6~H-5-bromo-20-methyl, 6~H-5,14-dibromo, 6~H-13,14-
didehydro-20-methyl and finally 6~H-5-bromo-13,14-&idehydro compounds and their
6~H-5-iodo (but not 6~H-5-iodo isomers) are very active 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
and myocardial infarct, in treatment of atherosclerosis, and in general in
all syndromes etiologically based on or associated with lipid imbalance or
hyperlipidemia, as well as in treatment of geriatric patients for prevention
of cerebral ischemic episodes, and inlong-term treatment after myocardial
infarct.
When the compounds of the invention are given as anti-aggregating
agents 9 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 PGF as standard.
~ `or example, Ln vitro, on the uterus of the estrogeni~ed rat, com-
pounds 6 H-6,9 -oxide-16-n!-chloro-phenoxy-~-tetranor and 6~H-6,9~-oxide-16-_-
.
3~ 35
-CF3-phenoxy~ -tet~anor, were 1.3 and 3.1 times as active as PGF2Cl. In the
in vivo assay, measuring the intrauterine pressure of the ovariectomized
rabbit, the same compounds were 5.9 and 8.25 times as active as PGF2Ci (see
the -following Table)
_,
in vitro in vivo
_ _
Uterus Ileum
PGF2 ci 1 1
6~H-6,9~-oxide-16-
m-chloro-phenoxy~ - ].3 0.05 5.9
tetranor
6~H-6,9~-oxide-16-
m-CF3-phenoxy-~- 3.1 0.1 8.25
tetranor
_
The table shows that the compounds have greater activity on the
uterus than on the gastrointestinal tract.
These compounds, which are useful for induction of labor, for expul-
sion of dead fetuses from the pregnant female, in either human or veterinary
medicine, are without the undesirable side effects of the natural prosta-
glandins, such as vomiting and diarrhea.
For this purpose the compounds of the invention can be given by
intravenous infusion, at a dose of about 0.01 ~g/kg/minute ~mtil the end of
labor. At the same dosage, the compounds o:E the invention dilate the uterine
cervix, facilitating therapeutic abortion and, in that situation are given
pre-Eerably in the form o:E vaginal tablets or suppositories.
Thc compounds of the invention, in particular the compound dl-6RII-
6,9ci-oxicle-16-m-chloro-pllenoxy-~-tetranor also have luteolytic activity and
~3~
36
are therefore of use for control of fertility.
The 6~H-6,9x-oxide and their 6~11-isomers were also investigated for
their action on the gastrointestinal tract, in order to know: ~a) cytoprotec-
tive activity against lesions induced by non-steroid anti-inflammatory drugs;
(b) ability to prevent the ulcers induced by the method of Togagi-Okabe [(Japan
J. Pharmac. vol. 18, 9 (1968)] and (c) antisecretory activity, according to
Shay et al Gastroenter. _, 906 (1954).
The 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 acetylene bon-1 is present in the 13,14-position; it is quadrupl-
ed when a 16-alkyl group, usually a methyl, is positioned in the 16(S)-con-
figuration.
As an ulcer-preventing substance, the parent 6~H-6,9~-oxide analog
is at least equipotent with PGE2 and the following substitutions, 13,14-
acetylene bond; 16S, or R methyl; 16S, or R fluoro, highly increase lup 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 6~11-6,9~-oxide-16-methyl-16-butoxy-~-
tetranor derivative.
For this purpose the compounds are preferably given by intravenous
injection or infusion, subcutaneously or intramuscularly. For intravenous
infusion, the doses vary frolll about 0.1 ~g to about 500 ~g/kg body weight/
millute. The total claily dose, either by injection or by infusion, is of the
I, ~
~ 37
order of O.l 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
routes: orally in the form of tablets, capsules, coated tablets or in liquid
form as drops or syrups; rectally in suppositories; intravenously, intra-
muscularly or subcutaneously; by inhalation, as aerosols or solutions Eor the
nebuli~er; by insufflation, in powdered form.
Doses of the order of 0.01-4 mg/kg can be given from 1 to 4 times
a day, with the exact dose depending on the age, weight, and condition of the
patient and on the route of administration.
For use as an antiasthmatic, the compounds of the invention can be
combined with other antiasthmatic agents, such as sympathicomimetic drugs like
isoproterenol, ephedrine, etc., xanthine derivatives, such as theophylline and
aminophylline, or cortico-steroids.
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 closage Eorms, e.g., orally in the
form of tablets, capsules or liquids; rectally, in -the form of suppositories;
parenterally, subcutaneously or intramuscula:rly, with intravenous administ-
ration be:ing l~reEerred in emergency situations; by inhalation in the form o:E
34~ 38
aerosols or solutions for nebulizers; in the form of sterile implants for pro-
longed action; or intravaginally in the form, e.g., of bougies.
The phartnaceutical or veterinary composi-tions containing the compounds
of the invention may be prepared in conventional ways and contain conventional
carriers and/or diluents.
For example, for intravenous injection or infusion~ sterile aqueous
isotonic solutions are preferred. For subcutaneous or intramuscukar injection,
sterile solutions or suspensions in aqueous or non-aqueous media may be used;
for tissue implants, a sterile tablet or silicone rubber capsule containing or
impregnated with the compound is used.
Conventional carriers or diluents are, for example, water, gelatineJ
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 of the invention, preferably in the form of a salt, such as the sodium
salt in water, can be used. Alternatively, the pharmaceutical preparation can
be in the form of a suspension or of a solution of the compound of the inven-
tion in one of the usual liquefied propellants, such as dichlorodifluoromethane-
or dichlorotetrafluoroethane, administered from a pressurized container such
as an aerosol bomb. When the compound is not 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 Eollowing examples, wherein the
abbreviations "TIIF", "DME", "DMS0", "T~IP", "~t20" refer to tetrahydroEuran,
d;.methoxyethane, dimethylsulphoxide, tetrahydropyranyl, and ethyl ether,
l~3
3~
respectively.
The following examples demonstrate preparation of both
final products of the invention and preparation of intermedia-tes,
but do not limit the present invention.
Example _
To a solution of 1.0 g of dl-5~-hydroxymethyl-2~,4~-
dihydroxycyclopentan-l~-acetic acid-~-lactone-4-p-phenylbenzoate
in 8 ml of benzene/DMSO (75/25) is added with stirring 0.89 g of
dicyclohexylcarbodiimide. At room temperature, 1.42 ml of a solu-
tion of pyridinium trifluoroacetate is added (prepared from 1 ml
of 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 solu-
tion, 0.3 g in 3.8 ml of water. After approximately 15 minutes
of stirring, the mixture is filtered, and the organic phase is
washed with water until neutral, concentrated to 2 ml, and then
diluted with 5 ml of isopropyl ether. The product is isolated by
filtration and crystallized from isopropyl ether to give 0.8 g 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 ~-toluenesulfonic acid monohydrate.
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 sa-turated
- 39 -
3~2
NaCl until neutral. The solvent is removed at reduced pressure and the resi-
due is crystallized from methanol to give 800 mg of dl-5~-dimethoxymethyl-2~,
4~-dihydroxy-cyclopentan-1~-acetic acid-y-lactone-4-_-phenylbenzoate, m. p. =
108 - 110C.
60 mg of ~2CO3 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
NaH2P04 solution. The methanol is removed and the residue taken up in ethyl
acetate. This is washed with saturated NaC] until neutral, is dried over an-
hydrous Na2S04, is filtered, and evaporated under reduced pressure to give
480 mg of dl-5~-dimethoxymethyl-2a,4~-dihydroxy-cyclopentan-1~-acetic acid-y-
lactone.
A solution of this in 4 ml of CH2Cl2 is treated with 0.32 ml of
2 J 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 5 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-tetrailydropyranyl ether.
Starting from a 4-ester of 5~-dimethoxymethyl-2~,4~-dihydroxy-cyclopentan-1~-
acetic acid-y-lactone ~for example: 4-_-phenylbenzoate, m. p. 128 - 130 C,
~D = -85) or from a 4-ester of 5~-hydroxymethyl-2~,4B-dihydroxy-cyclopentan-
lB-acetic-r-lactone (for example: the 4-E~phenylbenzoate, m. p. = 127 - 129C,
~ = +84.5), the same procedure was used to prepare the following compounds:
SB-dimethoxymethyl-2~,4~-dihydroxy-cyclopentan-lr-acetic acid-y-lactone-4-
tetrahydropyranyl ether and 5~-dimethoxymethyl-2~,4~-dihydroxy-cyclopentan-
lB-acetic acid-r-lactone-4-tetrahydropyranyl ether. If 1,4-diox-2-ene is used
instcad of 2,3-dihydropyran, the corresponding 4-dioxanyl ether derivatives
are obta;ned.
4~-
~38~
Example 2
A solution of 216 mg of 5~-dimethoxymethyl-2~,4~-dihydroxycyclopen-
tan-l~-acetic acid-y-lactone [~]D = -16 , [~]365= -48 (C = l.O CHC13~ in
1.6 ml of dimethylformamide is treated with 0.3 ml of triethylamine followed
~y 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 with water and dried over Na2SO4 to give 310 mg of 5~-dimethoxymethyl-
2~,4~-dihydroxycyclopentan-1~-acetic acid-~-lactone-4-dimethyl-tert-butylsilyl
ether.
Exam~
To a solution of dl-5~-hydroxymethyl-2~,4~-dihydroxycyclopentan-1~-
propanoic acid-~-lactone-4-_-phenylbenzoate (1 g) in 8 ml of benzene:DMSO
~75:25) 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 water 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 ~ith 0.59 ml of methylortlloformate and 17.3 mg of p-toluenesulfonic
acid. After appro~imately one hour, 0.01 ml of pyridine is added and the solu-
tion is cvaporated to dryness. The residue is ta]~en up in ethyl acetclte; the
organic phase is waslled with lN NaO~I and then saturated NaCl until neutral.
~vaporation to dryness gives 169 mg of dl-5~-dimethoxymethyl-2~,4~-dillydroxy-
cyclopentan-l~-propiollic acid-~-lactone-4-p-pilenylbenzoate. This is then dis-
solved in 5.4 ml of anhydrous methanol and 75 mg of K2CO3 is added. After
11~38~
four hours of stirring at room temperature and filtration, the solution is
reduced in volume and acidified with a saturated solution of NaH2PO4. 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 Na2SO4, and evaporated under vacuum to give crude dl-5~-dimethoxy-
methyl-2a,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~-dimethoxymet]-yl-2a,4a-dihydroxycyclopentan-1~-
propanoic acid-~-lactone-4-tetrahydropyranyl ether.
From a 4-ester of 5~-hydroxymethyl-2~,4a-dihydroxycyclopentan-la-
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-2a,4a-dihydroxycyclopentan-1~-propanoic acid-~-lactone-4-
tetrahydropyranyl ether;
5a-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-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.
Exam~le 4
A solution of 1 g of 5~-formyl-2~-hydroxycyclopentan-la-acetic
acid-~-lclctone in 6.5 ml of anhydrous methanol is treated with 1.74 ml of
methylorthoformate and 52 mg of _-toluenesulfonic acid. Aftcr approximately
one hour, 0.04 ml of pyridine is added and the solution is evaporated to dry
ness. The residue is taken up in ethyl acetate,and then \~ashed ~ith lN NaOH
3 ~
~B3~
and then saturated NaCl until neutral. Evaporation under vacuum gives 1 g of
5~-dimethoxymethyl-2~-hydroxycycloperltan-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.
Example 5
To a solution of 9G0 mg of dl-5~-dimethoxyJnethyl-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
dropwise. The solution is warmed to 0C and treated l~ith 3 ml of a 30% solu-
tion of NaH2PO4. After 1 hour of stirring, 12 g of anhydrous Na2S04 is added.
Filtration and evaporation of solvent gives 900 mg of dl-5~-dimethoxymethyl-
2~,4~-dihydroxycyclopentan-1~-ethanal-y-lactol-4-tetrahydropyranyl ether.
Example 6
Following the procedure of example 5, a solution of 400 mg of 5S-
dimethoxymethyl-2~4~-dihydroxycyclopentan-1~-acetic acid-y-lactone-4-dimethyl-
tert-butylsilyl ether in 11 ml of toluene, cooled to -70 C, 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~,4u-dihydroxycyclopentan-1~-ethanal-
y- lactol-4-dimethyl-tert-butylsilyl ether.
Example 7
Under a nitrogen atmosphere, a solution of 62S mg of 5~-dimethoxy-
mcthyl-2~,4~-dil-ydroxycyclopentan~ -propanoic acid-~-lactone-4-tetrahydro-
pyranyl ether in 11 ml of toluene, coolcd to -70C, is treated dropwise with
5.~ ml oE a 0.5M toluene solution of di-iso-butylaluminum hydride. After 30
n~ utes at -70C, 10.~ ml of a 2M toluene solution of isopropanol is added
,~3
3~
dropwise. The temperature is allowed to rise to 0C and 2 ml of 30% NaH2P04
is added. After one hour of stirring, 8.3 g of anhydrous Na2S04 is added and
the mixture is filtered. Evaporation of the organic phase under vacuum gives
620 mg of 5~-dimethoxymethyl-2~,4~-di}-ydroxycyclopentan~ 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; 4-dioxany] ether) and a 4-dimethylbutyl-
silyl ether of the following compounds are prepared:
5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-ethanal-1-lactol, in its
dl and optically active form (or nat-);
5~-dime~hoxymethyl-2~,4~-dihydroxycyclopentan-1~-ethanal~r-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 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 added, at -30C, to 0.98 g of
dl-5~-benzyloxymethyl-2N-hydroxycyclopentan-l~-propionic acid-~-lactone in 22
ml of toluene. After 45 minutes, excess reagent is quenched Wit]l 6 ml of a
0.5 hl toluene solution of isoprop?nol. The mixture is warmed to 0C, 4 ml of
30O 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~-ben~yloxymethyl-2~-}1ydroxycyclopentan-l~-
''~ prOpanal-~-lactol.
8~2
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~-benzyloxymethyl-2~-hydroxycyclopentan-1~-propanal-~-lactol;
5~-dimethoxymethyl-2~-hydroxycyclopentan-l~-ethanal-y-lactol;
5~-dimethox~nethyl-2a-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-l~-ethanal-y-lactol-4-tetrahydropyranyl ether. After the addition, the
mixture is held at room temperature for 1 hour and then diluted with 16 ml of
ice/water. The aqueous phase is extracted with ether ~5 x 8 ml) and ether:
benzene (70:30, 5 x 6 ml), the organic laycrs, after re-extraction with 0.5~l
NaOH (2 x 10 ml), are discarded. The combined alkaline aqueous phase is acid-
ified to pH 4.8 with 30% Nall2P04 and then extracted with ethyl ether:pentane
1, 5 x 15 ml); from the combined organic phases, after drying over Na2S04
and solvent removal, one obtains 0.45 g of 5-cis-7-(2'~,4'~-dihydroxy-5'~-
dimethoxymethylcyclopentan~ yl)-hept-5-enoic acid-4'-tetrahydropyranyl
ether. This in turn is converted to the corresponding methyl ester upon treat-
ment ~Yitll diazomethane in ether. An analytic sample is prepared by adsorbing
100 mg of the crude product Oll 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 H
le 11
In .m anhydrous nitrogen atmosphere, a suspension of 0.39 g of a
75u oil dispersion of Nall in DMSO (13.5 ml) is heated to 60 - 65 C for 3 1/2
4~Js-
~L~83~3~2
hours; after cooling to room temperature and while maintaining the reaction
mixture at 20 - 22C, the follol~ing are added, in order: 2.66 g of 3-carboxy-
propyltriphenylphosphonium bromide in 6 ml of DMSO and 0.6 g of 5~-dimethoxy-
methyl-2c~,4cl-dihydroxycyclopentan-lc~-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 NaH2PO4 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'~,4l~-
dihydroxy-5'~-dimethoxymethyl-cyclopent~ -yl)-hept-4-enoic acid. Treatment
with diazomethane affords the corresponding me-thyl ester.
Example 12
The methyl esters of the following acids were prepared from lact~ls
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-cis-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'c~-hydroxy-5'~-benzyloxymethyl-cyclopent-l'c~-yl)-hept-5-enoic;
5-cis-7-(2'~,4'c~-dihydroxy-5'3-dimethoxymethyl-cyclopent-l'c~-yl)~llept-5-enoic
and its 4'-dioxanyl, tetrahydropyranil and dimethyl-tert-butylsilyl)-ethers;
4-cis-7-(2'a,4'cl-dihydroxy-5'~-dimethoxymcthyl-cyclopent-l'(x-yl)-llept-4-enoic
and its 4'-(dioxanyl, tetrahydropyranyl and dimethyl-tert-butylsilyl)-ethers;
~/~
3~34~
Example 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 follol~ing bicyclic
derivatives 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-bicyclo[3.4.0]nonan-3'S-yl)-butanoic acid
methyl ester;
a 7'-acetal ether (tetrahydropyranyl ether, dioxanyl ether), and a 7'-dimethyl-
tert-butylsïlyl ether of 5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-
bicyclo[3.3.0]octan-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[3.4.0]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 solutlon of 0.4S g of bromine in 5 ml of methylene chloride is
added drop~ise, Wit]l stirring, to a solution of 0.27 g of pyridine and 1.2 g
o~ 5-cis-7-(2'~,4'~-dihydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)-hept-5-
~3~2
4-cis-6-(2'c~,4'cY-dihydroxy-5'~-dimethoxymethyl-cyclopent~ -yl)-hex-4-enoic
and its 4'-~tetrahydropyranylether;
5-cis-8-(2'cY,4'~-dihydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)oct-5-enoic
and its 4'-tetrahydropyranylether.
Example 13
A solution of 1.06 g of the methyl ester of 5-cis-7-(2'~,4'~-dihy-
droxy-5'~-dimethoxymethyl-cyclopent-l~cY-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 boorohydride 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-Ilydroxy-2'-oxa-
bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl
ether.
Example 14
A solution of 1.59 g of 4-cis-7-~2'cY,4'~-dihydroxy-5'~-dimethoxy-
methyl-cyclopent-lIcY-yl)-hept-4-enoic methyl ester-4'-tetrahydropyranyl ether
in 6 ml of THF is added to a solution of 1.26 g of mercuric acetate in 4 ml
of water diluted with 4 ml of T~IP. 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, wIlich is then waslled with TI-IF. The
aqueous/orgarIic decanted solution is concentrated under ~educed pressure and
the residue extracted with ethyl acetate. The combined organic extract, after
wasII:ing with ~ater until neutral, affords upon removal of the solvent 0.98 g
o.~ ~-(7'-exo-climctho~;ymethyl-8'-elldo-hydroxy-2'-oxa-bicyclo~3.4.0~nonan-3'~-yl)
l~utanoic acid ]nethyI ester-8'-tetrahyd ~ yranyl ether.
L838~Z
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 sodium 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 ether in 15 ml of carbon tetrachloride. The
mixture is stirred for 3 hours and 30 ml of ethyl ether is added. The organic
phase is washed l~ith 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 L 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 stirring, ethyl ether is added; the solution is then
~ashed with water, lN Na2S203, and ~ater until neutral. Evaporation to dry-
ness gi~es 0.98 g of 4-bromo-4-~7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-
oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid mcthyl ester-8'-tetrahydropyra-
nyl ether.
Example 19
To a suspension of 0.25 g of dry CCLCO3 in a solution of 346 mg of
5-cis-7-(2'~ ydroxy-S'~-~enzyloxymetllyl-cyclopent-l'~-yl)-hept-5-enoic acid
3l~ Z
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 2 hours the
inorganic salts are removed by filtration. The solution is washed with a 7%
aqueous solution of KI and Na2S203 and then with wa-ter until neutral. The
residue upon evaporation to dryness is adsorbed on silica gel and eluted ~ith
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.
Example 20
A solution of 0.39 g of 5-cis-7-(2'c~,4'c~-dihydroxy-5'~-dimethoxy-
methyl-cyclopent-l'c~-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 Na2S203 and then with
water until neutral. Removal of the solven~ 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-~?'c~,4'~-dihydroxy-5~-dimethoxymethyl-cyclopent-l'c~-yl)-hept-4-enoic acid
methyl ester-4'-tetrahydropyranyl ether and ~2 mg of pyridine in 10 ml of
CC14. Stirring is continued until the color disappears; 30 ml of ethyl ether
is then added. The organic phase is ~ashed with water then a solution 7%
in KI and Na2S203, and then water Imtil neutral. Removal oE the solvent af-
fords 0.48 g of 4-ioclo-4-(7'-exo-dimethoxymethyl-8'-elldo-ilydroxy-2'-oxa-
bicyclo~3.4.0]nonan-3' -yl)-butanoic acid methyl ester-8'-te-trallydropyranyl
ether.
~3313~
Example 22
To a solution of 0.34 g of S-cis-7-(2'~-hydroxy-5'~-benzyloxymethyl-
cyclopent~ -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 0052 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 with 80 mg of pyridine in 2 ml of CH2Cl~ and then dropwise with stirring
with a solution of 150 mg of Br2 in C-l2C12. After 20 minutes of stirring at
room temperature/ the organic phase is washed with water, then 7% ~i and
Na2S203, 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-3'1-yl)-pentanoic
acid methyl ester.
Mass spectrum M 424,426 m/e M -HBr 344 m/e M -CHBr (Cll2)3C02(CH3 = 231 m/e.
Example 23
10.5 mg of p-toluenesulfonic acid monohydrate is added to a solution
of 0.26 g of S-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo
~3.3.0~octan-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 solvent evaporation 0.23 g of crude 5-iodo-5-(6'-
exo-dimethoxymethyl-7'-endo-11ydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pen-
tanoic acid n~ethyl ester. Separation by chromatography on silica gel with
mothylcne chloride: ethyl ether (75:25) as eluent affords S4 mg of 5-iodo-5-
~J~2
--~6
3~
(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicycloL3.3.0]octan-3'-endoyl~-
pentanoic acid methyl ester and 55 mg of the 3'-exo isomer.
Referring the spectrometric data, the prostaglandin numbering will be used;
thus the a~ove diastereoisomers can be named as follows: the endo diastereo-
isomer: 5-iodo-6~H-6,9~-oxide-11~-hyd:roxy-12~-dimethoxy-formylacetal-~(20 -~ 13)
heptanor-prostanoic acid methyl ester and the exo diastereoisomer 5-iodo-6~H-6,
9~-oxide-ll~-hydroxy-12~-dimethoxy-formylacetal-~(20 -~ 13~1leptanor-prostanoic
acid methyl ester.
Analytical data:
endo diastereoisomer: TLC more polar-one spot
Mass spectrum (m/e; % intensity fragment): 442 0.002 M ; 412 4 M -CH2O,
315/314 3 M -iodine/lll 283 11 315-CH30H, 75 100 CH 3
~ OCH3
N.M.R. (solvent CDC13, TMS internal standard) p.p.m.:
",OCH
3 49 and 3 52 s 3H/3H CH 3 ; 3 64 s 3H CO CH
4.00 m, 3H (protons at C5, Cg, Cll); 4.29 d, lH, -Cll
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.], 55.5, 83.1,
41.5, 74.2, 44.6, 108.0J 54.2, 54.1, 51Ø
exo diastereoisomer: TLC less polar-one spot
Mass spectrum: 442 0.01 M , 366 3 M C~12Ci-l(OCII3)2,
315 4 M -1; 283 10 M -l-CII3OH; 75 100 CH(OCII3)2
, " OC~17
N.M.R.: p.p.m. 3.34 and 3.37 3H/3H s C ; 3.5 and 4.1
OC113
m llIclnd 211 protons at C5, C9, Cll uncertain assignment,
, OCI 1~
3.65, s 3II, C02CI-I3; 4.21, dllI, CH ~; 4.35 m, lH,6~H
- OC113
1~
~.838~:
CMR: p.p.m. 173.0, 37.0, 33.1, 25.5, 40.1, 84.4, 39.7,
57.2, 83.7, 40.5, 75.9, 44.0, 107.3, 54.0, 53.8, 51.1.
Example 24
A solution of 980 mg of 4-bromo-4-(7'-exo-dimethoxymethyl-8'-endo-
hydroxy-2'-oxa-bicyclo[3 4.0]nonan-3~7-yl)-butanoic acid methyl ester-8t--
tetrahydropyranyl ether i.n 6 ml of anhydrous methanol is treated at room
temperature for 30 minutes with 4S mg of _-toluenesulfonic acid. 2% aqueous
NaHC03 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 halocyclization as described in one of the examples
16 to 22, the following halobicyclic compounds are prepared:
5-chloro-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-
3'i-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether (and 7'-di-
oxanyl ether and 7'-dime~hylbutylsilyl ether);
4-chloro-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-
3'1-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;
5-chloro-5-(6'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pen-
tanoic acid methyl ester;
~-chloro-~-(7'-exo-dimethoxymetllyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-
~3
~r ~r~ ~
3i 391~
butanoic acid methyl ester;
4-chloro-4-~7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3' 7 -yl) -butanoic
acid methyl ester;
5-bromo-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 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 8'-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-2' oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic
acid methyl ester;
4-bromo-4-(7'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.4.0]nollan-3',-yl)-butanoic
acid methyl ester;
4-bromo-4-(7'-exo-ben~yloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic
acid-methyl ester;
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 (and 7'-di-
oxanyl and 7'-dimethyl~utylsilyl esters);
4-iodo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo~3.4.0]nonan-
3'~-yl)-butanoic acid methyl ester-8'-tetral-ydropyranyl ether (and 8'-di-
oxanyl and 8'-dimethylbutylsilyl ethers);
5-iodo-5-(6'-exo-dimethoYymetl-yl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic
acid methyl ester;
5-iodo-5-(6'-exo-ben~yloxymetl-yl-2'-oxa-bicyclo[3.3.0]octan3'~-yl)-pentanoic
acicl methyl ester;
4-ioclo-4-~7'-exo-bcn~yloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'5-yl)-butanoic
~L~l831341,;~:
acid methyl ester;
4-iodo-4-(7'-exo-dime~hoxymethyl-2'-oxa-bicyclo[3.4.0]nonan-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 procedure in examples 23 and 24 af-
fords the 3'~-oxiran-hydroxide-formyl acetal deri.vatives, ~hich 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-(71-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)-pentanoic acid methyl ester, and its individual 3'-exo and 3'-endo
isomers;
endo isomer: TLC on SiO2 more polar one spot
~CH7
N.M.R.: (CDC13) p.p.m. 3.4 d,6H, CH OCII ; 3.65, s,3H CO2C1~3
J ~ OC~13
4.00 m,4H (protons at C4, C5, Cg, Cll); 4.17 d,l, CH OCH
4.5 m~ lH, 6~H
ChlR: 173,0, 35.0, 33.3. 23.6, 59.4, ~0.6, 36.4, 55.6, S3.3,
41.6, 74.3, 44.5, 10~.0, 54.4, 54.2, 51.1
exo isomer: TLC an Si.O2 less polar isomer one spot
, OCI-I
N-M-R-: (CDC13) p-p-m-: 3.37 d,6H -CH OCII ; 3.66 s,3~1,CO2CH~
~ OCH_
4.00 m,4ll, protons at C4, C5, C9, Cll; 4-2 d,l, -Cl-l OCI{
4.3~ m,lll, 6aH
S
33~
C~IR: 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'-exo-dimet}loxymethyl-8'-endo-hydroxy-2~-oxa-bicyclo[3.4.0]noncm-
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-~-~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 2.8 g of tributyltin hydride in 8 ml of benzene. The mixture
is held at 55C for 8 hours and then overnigi-t at room temperature. The ben-
zene layer is washed with 2 x 10 ml of a 5~ NallC03 solution and then with
water until neutral. The residue upon solvenl 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'-tetrahydropyranyl ether.
Example 28
60 Ing of ~-toluenesulfonic acid is added to a solution of 1.98 g of
5-~6'-exo-ditnethoxymethyl-7'-endo-hydroxy-2'-oxa-bicycloL3.3.0]octan-3'~-yl)-
pentano;c acid metl~yl ester-7`'-tetrallydropyrallyl ether in 10 ml of anhydrous
methanol. Aftcr 30 minutes at room temperature, this is added to 20 ml of
20o aqucous NallC03. The mlxture is extracted witll ethyl ether; the combined
3~J~
ether extract, after drying over ~a2SO~, 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-dimethoxymethyl-7'-endo-
hydroxy-2'-oxa-bicyclo[3.3.0]octan-37-exo-yl)-pentanoic acid methyl ester,
0.52 g of the 3'-endo isomer and 0.12 g of 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,lH 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, after 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[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester-8'-tert-butyl-
methylsilyl ether in 10 ml of anhydrous methanol is treated with 55 mg of p-
toluenesulfonic 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. Chromatograplly of this on silica
gel with benzene: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).
Examplc 30
Using the proccdure in examples 28 and 29, mcthanolysis of the
cthcrs ~acetal or silyl) described in example 15 gives the corresponding free
alcohols.
p ~
~131~
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 3~1/3H
CH OCH; 3.66 s 3H CO Cl-13 ; 4.00 m 21-1 protons at
--3 _ _
~ OCH3
5 9;-~OCH3 ; 6 m 111 6~H 5.0 m lH
proton at Cll
~The spectrometric data for the 6~H isomer acetate are respectively the
following 2.03; 3.34 - 338, 3.66 s~m 4H CO2CII~ and one of C5, C9 protons
4.1 m lH other of C5, C9 protons 4.2, 4.4 m 111 6~ 5.1]. A solution of the
5-iodo-3'-endo-acetate in benæene ~5 ml) is treated with 0.4 g of tributyltin
hydride for lO hours at 50C. After the benzene phase is washed with 5%
NaHCO3 and water, evaporation of the solvent and purification on silica gel
(10 g) with a benzene:ethyl ether ~80:20) eluent afford 0.105 g of 5-~6'-
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 which halogen is replaced by hydrogen.
These are identical in evcry way with the compounds prepared according to the
procedures of examples 15, 28, 2~ and 30.
Example 33
5.4 mg of hydroquinone and a solution of 1.63 g of oxalic acid in
48 ml of water are added to a solution of 4 g of 5-~6'-exo-dimethoxymethyl-
7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'S-yl)-pentanoic acid methyl
ester in 180 ml of acetone. After 12 hours at ~0 C, the acetone is removed
at reduced pressure and the mixture is extracted with ethyl acetate (3 x 25
ml). The combined 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[3.3.0loctan-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
Using the procedure of example 33, starting from the corresponding
bicyclo[3.3.0]octan-6'-exo-dimethoxymethyl and bicyclo[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
ester;
4-(7'-exo-formyl-2'-oxa-bicyclo[3.~.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;
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-formyl-7'-endo-}lydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-
pentanoic acid methyl ester;
~-chloro-~1-(7'-e~o-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-
~utanoic acid methyl ester;
3~-
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-2f-oxa-bicyclo[3.4.0]nonan-3'-yl~-butanoic acid
methyl ester;
5-bromo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]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)-
~utanoic 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-
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 methyl ester.
~xample 35
rO a solution of 1.2 g oE 5-(6'-exo-benzyloxymethyl-2'-oxa-bicyclo
[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester in methanol:metllyl acetate
~la ml:10 ml) is added 2 ml o~ a O;lN methanol solution of IICl. After 0.15 g
~C~
_ ,~ _
IL~
,. ..
3~3~L2
of PtO~ 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 l~ashing 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-
2'-oxa-~icyclo[3 3.0]octan-3'~-yl)-pentanoic acid methyl ester. This is then
oxidized to ~he 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~
dihydroxy-cyclopent-l~-acetic acid-y-lactone-4-tetrahydropyranyl ether in 150
ml of toluene cooled to -70C is added in 30 minutes 128 ml of a 5M solution
of di-iso-butylaluminum hydride (1.2M/M). After 30 minutes at -70 C, 128 ml
of a 2~1 toluene solution of isopropanol is added and the solution is brought
to 0C. Then 10 ml of a saturated aqueous solution of Nall2P04 is added and
the mixture is stirred for four hours. Following the addition of 10 g of
anhydrous Na2SO4 and 10 g of filtering earth, the solution is filtered and
evaporated to dryness to give 18.1 g of 5~-tetrahydropyranyloxymethyl-2a~4~-
dihydroxy-cyclopent-l~-ethanal-~-lactol-4-tetrahydropyranyl ether. A solution
of this in 24 ml of anhydrous DMSO 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 60 C. Then after the mixture is brought to 18 - 20 C,
67 g of 4-carboxybutyltriphenyl phosphonium bromide dissolved in 80 ml of an-
hydrous DMSO is added wllile maintaining a temperature of 20 - 22C to generate
a brigilt red color. Aftcr four hours of stirring, 600 ml of ~ater is added
and the mixturc is c~tracted with ethyl ether:benzenc ~70:30) to remove the
triphenylpllosphille oxidc. The ben~ene organic phase is re-extracted with
0.lN NaO~ and then with water until neutral; it is -then discarded. The
alkaline aqueous phase is acidified to p~l 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-5-enoic acid-4'-tetrahydro-
pyranyl ether, ~hich may be converted to its methyl ester by treatment with
diazomethane in ether. 7.72 g o~ this ester in 28 ml of tetrahydrofuran is
added dropwise to a yellow-brown suspension formed by adding 28 ml of T~l~ to a
solution of 6.13 g of mercuric acetate in 28 ml of water. After the mixture
is stirred for 20 minutes at room temperature, it is cooled in an ice:water
bath and 810 mg of NaBH4 in 14 ml of water is added dropwise. Elemental mercury
precipitates out, the suspension is decanted, the tetrallydrofuran 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-
2l-oxa-bicyclo~3.3.0]octan-3';;-yl)-pentanoic acid methyl estcr-7'-tetrahydro-
pyranyl ether; 0.42 g of _-toluenesulfonic acid is then addecl 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-bicyolo[3.3.0]octan-3'-exo-yl)-
2a 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'~-dihydroxy-5'~-tetrahydropyranyloxymethyl-cyclopent-1~-yl)-
hept-5-enoic acid-4'-tetrahydropyranyl ether in Cll2C12:CCl~ (10 ml:l0 ml) and
the resul~ing mixture is stirred -for four hours. 30 ml of anhydrous methanol
containing l~n mg of ~-toluenesulfonic acid is addcd and stirring is continucd
for anothcr 2 hours. 0.2 ml of pyridine is added, the mixture is reduced to
sm;lll volulne, and the residue is taken up in ~ater/ethyl acetate. After
as111ng wi~11 Na~S203 and then water until neutral, tlle organic phase is evap-
~38~;2
orated to dryness to give a residue tha~ 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.
Example 38
~ ollowing the procedure of example 37, but using the methyl ester
instead o 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 in~o the 3'-exo 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~ -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:C~I2C12 (1:1) is added. 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 p-toluene-
sulfonic acid. The solution is then concentrated, diluted with water, and
extracted with ethyl acetate. Removal of 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 thc 3'-endo isomer.
Example 40
.
To a solution of 0.356 g of 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 of benzene:~MS0 ~75:25) are added, in order, 0.2S g of dicyclohexyl-
car~o(liimldc and 0.4 ml of a pyridinium trifluoroacetatc solution (see example
1). After 3 hours of stirring, 8 ml of benzene and then aqueous oxalic acid
(94 mg in l.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 is 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 of dimethoxyethane is added. In 10 minutes this
is diluted ~ith 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(9a)-oxide-lla-hydroxy-15-
oxo-prost-13-enoic acid methyl ester and 0.98 g of 5-[6'-exo-(3"-oxo-oct-1"-
trans-en-l"-yl)-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl]-pen-
tanoic acid methyl ester or 13t-6aH-6(9a)-oxide-lla-hydroxy-15-oxo-prost-13-
enoic acid me-thyl ester, plus 0.9 g of a 1:1 mixture of the two isomers (3'-
exo and 3'-endo, or 6a~[ and 6~l-l). This last mixture is separated into its
two isomer:ic components by thin layer chromatography ~ith ethyl ether. They
sho~ the follo~ing absorptions, respectively:
~ ~83~
~ MeOH = 230 m~; ~ = 13JO7O; ~ MeOI = 228 m~, ~ - 12,200.
N-M-R- (CDC13) 0.9 t 3H C20-CI13, 3.68 s 3H CO2CH3, 6.16
d lH vinylic proton at C14 ~JHl4-Hl5
6-71 q lH vinylic proton at C13 (JH13 z
By the same procedure, from the corresponding 5-H and 5-halo com-
pounds, the following prostenoic acid derivatives are prepared:
13t-6c~H-6(g~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6(9c~)-oxide-5-chloro-15-oxo-prost-13-enoic acid methyl ester;
13t-6aH-6(9c~)-oxide-5-bromo-15-oxo-prost-13-enoic acid methyl ester;
13t-6c~H-6(9c~)-oxide-5-lodo-15-oxo-prost-13-enoic acid methyl ester;
13t-6c~H-6(9c~)-oxide-5-chloro-llct-hydroxy-15-oxo-prost-13-enoic acid methyl
ester;
13t-6clH-6(9c~)-oxide-5-bromo-llci-hydroxy-15-oxo-prost-13-enoic acid methyl
ester,
N.M.R. = 3.67 s 3H CO2CH3; 3.95 m 4H C5, Cg, Cll protons and Hx/Hy proton at
C4; 4.3 m lH 6c~H; 6.15 d lH C14 proton; 6.63 q lH C13 proton;
13t-6clH-6(9c~)-oxide-5-iodo-llc~-hydroxy-15-oxo-prost-13-enoic acid methyl
ester,
N.M.R. 0.9 s 3H C20CH3, 3.53 m lH proton at C5, 3.6 s 3H C02CH3 3.9 m H
protDn at C4, 4.1 m 2H proton at C9, Cll; 4.4.m 11-1 6c~H; 6.2 d lH proton at
C14 6-75 q lH proton at C13;
13t-6~H-6C9c~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6(9c~j-oxide-5-chloro-15-oxo-prost-13-enoic acid methyl ester;
13t-6~1-1-6(9~)-oxide-5-bromo-15-oxo-prost-13-enolc acid methyl ester;
13t-6~H-6~9c~-oxide-5-iodo-15-oxo-prost-13-enoic-acid methyl ester;
13t-63H-6~9~)-oxide-5-chloro-llc~-hydroxy-15-oxo-prost-13-enoic acid methyl
ester;
1 ~7~ ~
313~
13t-6~H-6~9~)-oxide-5-bromo-11~-hydroxy-15-oxo-prost-13-enoic acid methyl
ester,
N.M.R.: 3.65 s 3H CO2CJ-13; 4.00 m 3H proton at C5, C9, Cll, 4.6 m 1~1 6~11;
6.2 d lH proton at C14; 6.64 q lH proton at C13;
13t-6~H-6~9~)-oxide-5-iodo-11~-hydroxy-15-oxo-prost-13-enoic acid methyl
ester;
N.M.R. 3.66 s 3H CO2CH3, 3.96 m 311 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.
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 Na~l (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-3'3-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 with benzene. The organic layers are com-
bined and evaporated to dryness. The residue is purified on silica gel (50 g)
~ith 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-
hydroxy-15-oxo-prost-13-enoic acid methyl ester and 1.45 g of 4-bromo-4-
I7'-exo-~3"-oxo-oct-1"-trans-1"-enyl)-8'-endo-llydroxy-2'-oxa-bicyclo[3.4.0]
nonan-3'--e~o-yl~-butanoic acid methyl ester or 13-trans-4-bromo-5~l-5(9~)-
oxide-ll~-hydroxy-15-oxo-prost-13-enoic acid methyl cster. ~letilanolic solu-
tions of these t~o compounds absorb in the lJV at
A maxl ~ 230 m~, E = 10,640, and ~ nnax~l = 229 m~, ~ = 11,600, respectively.
'7~ _
8~'~
The same procedure, starting from the 4-H and 4-halo bicyclo deriva-
tives, gives the following prostenoic acids:
13-trans-5~H-5(9~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-5~H-5(9~)-oxide-11~-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(9~)-oxide-11~-hydroxy-15-oxo-prost-13-enoic acid
methyl ester;
13-trans-4-bromo-5~H-5(9~)-oxide-15-oxo-prost-13-enoic acid methyl es*er;
13-trans-4-bromo-5~H-5(9~)-oxide-11~-hydroxy-15-oxo-prost-13-enoic acid
methyl ester;
13-trans-4-iodo-5~H-5(9~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-iodo-5~H-5(9~)-oxide-11~-hydroxy-15-oxo-prost-13-enoic acid methyl
ester;
13-tr -5~H-5(9~)-oxide-15-oxo-prost-13-enoic acid methyl es*er;
13-trans-5~H-5(9~)-oxide-11~-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-chloro-5~H-5(9~)-oxide-15-oxo-prost-13-enoic acid methyl ester.
13-tr -4-chloro-5~H-5~9~)-oxide-11~-hydroxy-15-oxo-prost-13-enoic acid
methyl ester;
13-trans-4-bromo-5~H-5~9~)-oxide-15-oxo-prost-13-enoic acid nnethyl ester;
13-trans-4-bromo-5~H-5~9~)-oxide-11~-hydroxy-15-oxo-prost-13-enoic acid
methyl ester;
13-trans-4-iodo-5uH-5(9~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-iodo-5~H-5(9~)-oxide-ll~ hydroxy-15-oxo-prost-13-enoic acid methyl
ester.
Example 44
By tilC procedure of example 42, the reaction of 620 mg of (2-oxo-3-
metllyl-4-butoxybutyl) phospllonate with 74 mg o~ Nal-l (75~) and 0.43 g of 5-(6!-
e~o-~ormyl-7'-endo-hydroxy-2'-oxa-bicyclo~3.3.0]octan-3' -yl)-pentanoic acid
.,_.. r ,
~8;384~
methyl ester in dimethoxyethane gives, after chromatography on silica gel
(25 g) with 1:1 ethyl ether:hexane as eluent, 0.15 g of 13t-6~H-6(9~)-oxide-
lla-hydroxy-l5-oxo-l6-methyl-l6-butoxy-l8~l9~2o-trinor-prost-l3-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 -H2O;
+ C~3
m/e 379 M -OCH3; m/e 295 M -115, m/e 115 ~O-C4Hg -
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(9c~)-oxide-llCl-hydroXy-15-oXo-16-]nethyl-16-butoxy-18,19,20-
trinor-prost-13-enoic acid methyl ester;
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~ ydroxy-15-oxo-16-methyl-16-butoxy--18,19,20-
trinor-prost-13-eno:ic acid methyl ester.
Example 46
To a suspension o~ 45 mg of 80% NaH in 10 ml of benzene is added a
~'( '' ,~
33~
solution of 375 mg of ~2-oxo-3,3-dimethyl-heptyl)--dimethylphosphonate in lO
ml of ben~ene, followed 30 minutes later by a solution of 0.305 g of 5-iodo-
5-~6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl
ester. 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-o~o-16,16-dimethyl-
prost-13-enoic acid methyl ester and 0.095 g of 13t-5-iodo-6cYH-6(9c~)-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-6~9c~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-6~H-6~9~)-oxide-llc~-hydroxy-15-oxo-16,16-dimethyl~prost-13-enoic acid
methyl ester;
13t-5~H-5~9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5~H-5~9c~)-oxide-ll~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid
methyl ester;
13t-5-chloro-6~H-6~9c~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl
ester;
13t-5-chloro-6~H-6~9~)'oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13~enoic
acid methyl ester;
13t-4-chloro-5~H-5~9c~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid me-thyl
ester;
13t-4-chloro 5~l-l-5(9c~)-oxide-llcl-hydroxy-l5-oxo-l6~l6-dimethyl-prost-l3
enoic acid metllyl ester;
13t-5-~romo-6~1-l-6~91)-oxicle-15-oxo-16,16-dimetllyl-prost-13 enoic acid methyl
~7
338~2
ester;
13t-5-bromo-6~H-6(9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic
acid methyl es~er;
13t-4-bromo-5~H-5(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl
ester,
13t-4-bromo-5~11-5~9~)-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-6~H-6(9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-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-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic
acid methyl ester;
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(9~)-oxide-15-oxo -16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5~H-5(9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid
methyl ester;
13t-5-chloro-6~H-6(9~-oxide-15-oxo-16,16-dimet}lyl-prost-l3-enoic acid me-thyl
ester;
13t-5-chloro-6c~H-6~9~)-oxide-11C~ ydroxy-15-oxo-16,16-dimethyl-prost-13-enoic
acid methyl ester;
13t-~-chloro-5~1-1-5(9~)-oxide-15-oxo-16,16-dimetllyl-prost-13-enoic acid methyl
ester;
13t-~-chloro-5~l~-S(9~)-oxide-ll~-hydroxy-15-oxo-16,16-dimethyl-prost-l3-enoic
3313~2
acid methyl ester;
13t-5-bromo-6~H-6~9~)-oxide-15-oxo-16,16-dimethyl-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-5~9a)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl
ester;
13t-4-bromo-5~H-5(9~)-oxide~ -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~-6~H-6(9~)-oxide-11~-hydroxy-15-oxo-16~16-dimethyl-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-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic
acid methyl ester;
Example 48
To a suspension of 178 mg of NaH ~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]-dîmethylphosphonate in 10 ml of anhydrous benzene.
After 30 minutes of stirring, a solution of 1 g of 5-(6'-exo-formyl-7'-endo-
hydroxy-2'-oxa-bicyc]o[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester is
added and stirring is continued for another hour. ~he mixture is neutralized
ith 30O aqueous Na~l2P04, and the organic phase is separated, concentrated
and adsorbed on silica gel. Elution with CEI2C12:Et20 (90:10) gives, 0.62 g of
13t-6~EI-6(9~-oxide~ -hydroxy-15-oxo-16~S,R)-fluoro-17-cyclohexyl-18,19,20-
trinor-prost-13-enoic acid methyl ester
7~
.~
3~
~ eO~I = 238 m~, e = 12,765) and 0.31 g of the 6~H isomer (~ MeO = 238 m~,
F = 9, 870).
The N.M.R. data for the former compound are the following (CDC13) p.p.m.
3.64 s 3H CO2CH3, 3.8 m lH Cg proton, 4.03 q lH proton at Cll, 4.3 m lH 6~H,
5.00 and 5.55 t,t 1/2 H, 1/2 H proton at C16 JHF 55 }Iz, 6.54 q lH proton at
C 6 9 q 1~1 protOn at C13 JH14-H12 H13-H12 13
Treating this compound with pyridine and acetic anhydride it is converted into
the ll-acetoxy derivative, for which N.M.R. data are: (CHC133 p.p.m. 2.02
s 3H OCOCH3, 3.64 s 3H CO2CH3, 3.8 proton at Cg, 4.25 m lH 6dH; 4.66, 5.22
t.t. 1/2 H, 1/2 H proton at C16; 4.97 q lH proton 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 n/e and then M -H20, ~ -HF, ~f -CH30H/CH20
M -CH2=CHOH (basis ion) M 115 M -44-59 and M -(CHF-CH2-C6Hl~)
In mass spectrum of exo-diastereoisomer the follo~ing masses are predominant:
M -CH30H and M -44-28; in that of endo-diastereoisomer the predominank ones
are M -CH30 and M -44-18.
From the 5-hromo derivative, 13t-5-bromo-6~H-6~9a)_oxide-11~-hydroxy-
15-oxo-16(S~R)-fluoro-17-cyclohexy1-18,19,20-trinor-prost-13-enoic acid
methyl ester is prepared.
Example 49
Substituting 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 ~ere prepared:
~ ~3 ~
~3~3~2
13t-6~,1{-6(9c~)-oxide-llcY-hydrox~-15-oxO-17-cyclohexyl-18,19,20-trinor-prost-
13-enoic acid methyl ester,
13t-6~H-6(9c~)-oxide-llcl-hydroxy-15-oxo-17-phenyl-18>19,20-trinor-prost-13-
enoic acid methyl ester and their 6c~H isomers.
Example 50
To a suspension of 178 mg of NaH (75% mineral oil dispersion) in
anhydrous tetrahydrofuran at 0C is added dropl~ise with 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-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid me~hyl
ester is added and stirring is continued for another hour. The mixture is
acidified with aqueous NaH2PO4, the organic phase is separated, and the aque-
ous phase is re-extracted with benzene. From the combined organic extract,
after chromatography on silica gel with CH2C12:Et2O (95:5) as eluent, one
obtains of 0.43 g of 13t-6c~H-6(9c~)-oxide-llc~-hydroxy-15-oxo-16-_-chloro-
phenoxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester
(~ ~leO~I = 227 m~, ~ = 16,800) and O.l] g of the 6~H isomer (~ ax = 224 m~,
F = 16,900).
Both the diastereoisomers show the mass peak m/e 436 according to
C23H29ClO6. This ion is involved in the following fragmentation:
M -H2O, M OCI13/Ctl30H, M -44, M -(O-C6H4Cl), M -H2O-(O-C6H4Cl) and
M -CCH2)4-Co2CH3, so furthermore confirming the propGsed structure.
The following differences are between the two diastereoisomers: the exo 6c~H
isomer shows a peak at M -32 ancl a little intense peak at M -44 on the other
hancl the endo 6~11 isomer shows a peak at M -31 and an intense peak M -44.
E~ample 51
The substitution of a phosphonate chosen from 2-oxo-3-(_-trifluoro-
7~
3~
met~lylphenoxy)-propyl-dimethylphosphonate and 2-oxo-3-(p-fluorophenoxy)-
propyl-dimethylphosphonate in the procedure of example 50 leads to the follow-
ing compounds, respectively:
13t-6~H-6~9~)-oxide-11~-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-p-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 ~F3-C6H4-0
are in the endo-isomer.
Example 52
The substitution of ~2-oxo-3S-methyl-butyl)-dimethylphosphonate for
the phosphonate in the procedure of example 4S gave 13t-6~1-1-6(9~)-oxide-11~-
hydroxy-15-oxo-16S-methyl-prost-13-enoic acid methyl ester and its 6~H isomer.
To a solution of 2.2 g of the 6~1 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-6~1-1-6~9~)-oxide-
hydroxy-15-oxo-16S-methyl-prost-13-enoic acid methyl ester-ll-acetate
MeO~I = 229 m~, ~ = 12,050)-
max
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
light orange color appears. 1.52 g of anhydrous potassiwn carbonate is then
added an(l thc resulting mixture is held at 80C for '~ - 5 hours to complete
the prccipita-tion of potassium bromide. E~cessacctic acid is removed under
vacuum, ~ater 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-11~-hydroxy-14-bromo-15-oxo
16S-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. ].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 6~11 isomer. Upon treatment with
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 mada by the procedure of example 52.
Exam~
~ solution oE 0.43 g of C2-oxo-octyl)-dimcthylpllosphonate in 10 ml
of benzene is added dropwise to a suspension of 54 mg of Na~l (80o mineral oil
dispersion) in 5 m:L of benzene. After 1 hour, when the evolution of H2 has
ccascd, 0.32 g of n-bromos~lccinimide is added all at once. To the carbanion
tllus prepared, of (l-bromo-2-oxo-octyl)~dimetllylp}lospllonate is added a solution
3~2
o~ 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 quenched by the addition of 20 ml of a 10% solution of NaH2P04.
The organic phase, after being washed until neutral, gives 0,31 g of
13t-6~H-6~9~)-oxide~ -hydroxy-14-bromo-15-oxo-20-methyl-prost-13-enoic acid
methyl ester; this is then separated into the 6~H 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-6~9)-oxide-lla-hydroxy-14-bromo-15-oxo-17-cyclohexyl-18,19,20-
trinor-prost-13-enoic acid methyl ester;
13t-6~H-6(9a)-oxide-11~-hydroxy-14-bromo-15-oxo-17-phenyl-18,19,20-trinor-
prost-13-enoic acid methyl ester.
Example 56
By substit~lting 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-fornyl-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-5-iodo-6~H-6(9~)-oxide~ -hydroxy-14-bromo-15-oxo-16S-methyl-prost-13_
enoic acid methyl ester;
13t-4-iOdo-5~H-5~9a)-oxide-11~-hydroxy-14-bromo-15-oxo-16S-methyl-prost-13-
enoic acid methyl ester;
13t-5~ 5~9~oxide-11-hyd~oxy 14-bromo 15-oxo-16S-methyl-pTost-13-enoic
acid methyl ester;
~384~
13t-5-iodo-6~H-S(9~)-oxide~ -hydroxy-14-bromo-15-oxo-20-methyl-prost-13-
enoic acid methyl ester;
13t-4-iodo-5~H-5(9~)-oxide-11-hydroxy-14-bromo-15-oxo-20-methyl-prost-13-
enoic acid methyl ester;
13t-5~H-5(9~)-oxide-11~-hydro~-14-bromo-15-oxo-20-methyl-prost-13-enoic acid
methyl ester;
13t_5_iodo-6~H-6~9a~_oxide-ll~-hydroxy-14-bromo-15-oxo-17-cyelohexyl-18,19 J
20-trinor-prost~13-enoic acid methyl ester;
13t-5~H-5(9~)-oxide-11-hydroxy-14-bromo-15-oxo-17-cyclohexyl-18,19,20-
trinor-prost-13-enoic acid methyl es~er,
13t-5-iodo-6~H-6(9a)-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-11~-hydroxy-14-bromo-15-oxo-17-phenyl-18,19,20-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 DMS0 is added to a solution of 0.15 g of potassium t-butylate in 3 ml
of DM50 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 of stirring, an equal volume of water is added ar.d the mixture is
extracted with ethyl ether. The combined organic extract is washed until
neutral and the solvent is evaporated. Chromatography on silica gel (oyclo-
hexane:ethyl ether, 40:60) gives 0~21 g of 13t-6~1-6(9)-oxide-11~-hydroxy-
15-oxo-20-methyl-prost-13-enoic acid methyl ester.
7~ -
~3313~2
Subsequent preparative thin layer chromatography (SiO2-Et20) allows separation
of the 6~H and 6~1 isomers.
Example 58
A solution of d,l-13t-6~H-6~9~)-oxide-11~-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, ~he excess reagent is decomposed by
cautious addition of saturated NaCl solution 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 o~ 13t-6~H-6~9~)-oxide-ll~,lSR-dihydroxy-prostenoic acid
methyl ester, as an oil, and 0.42 g of d,l-13t-6~H-6(9~)-oxide-11~,15S-di-
hydroxy-prostenoic acid methyl ester, m.p. 69 - 71 C (mass spectrum m/e
350 M -18, 319 M -18 -CH30; 318 M -18-CH30H). A solution in methanol (4 ml)
of this ester i~ treated with 60 mg of lithium hydroxide and water (0.8 ml)
for 8 hours at room temperature. The methanol is removed in vacuum, the
residue is diluted with water and extracted with ethyl ether to remove
neutral impurities. The alkaline phase is treated with aqueous saturated
NaH2P04 solution until to pH 5 and then extracted with ethyl ether. The
later organic phases are collected to yield after evaporation of the solvents
the free acid d~l-13t-6~I-6(9~)-oxide-11~,15S-dihydroxy-prostenoic acid, m.p.
105 - 106 C. The 15R-hydroxy compound is a non-crystalli3able oil.
In the same way using nat-keto compound in the reduction reaction
with Zn(B~I4)2 we obtained besides the 15-epi alcohol, the nat-13t-6~}1-6(9~)-
oxide-11~,15S-dihydroxy~-prostenoic acid methyl ester, m.p. 71 - 72 C [~]D =
~ 10.2 ~ [~]365 = + 32.2 (CIIC13) and after saponification the free acid
m.p. 101 - 102 C [~D = + 6-34 J [~]365 = + 33-2 ~CI-IC13)-
_~
8~Z
Starting from the endo-diastereoisomers (more polar compounds),
the following esters were obtained:
13t-6~H-6(9~)-oxide-ll~,lSR-dihydroxy-prostenoic acid methyl ester (d,l, nat-,
ent- oils~;
13t-6~H-6(9~ oxide-11~,155-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-6~H-6~9~)-oxide~ ,15R-dihydroxy-prostenoic acid (d,l, nat-, ent- oils);
13t-6~H-6~9~)-oxide-llu,15S~dihydroxy-prostenoic acid (d,l oil, nat-, m.p.
78 - 80 C [a]D = + 32-5 , [~]365 ~ ~ 11-6 (EtOI-I), ent- m-p- 78 - 79 C,
[~]D = ~ 31 (EtOH))-
Example 59
~ith the temperature of the reaction mixture kept at around -5 to
-8 C, a solution 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 (7 ml); then, under
stirring, a solution of 0.35 g of 13t-6~H-6(9~)-oxide-11~-hydroxy-15-oxo-
16(S,R)-fluoro-17-cyclohexyl-18,19,20-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 Cll2C12-ethyl ether
70:30 as el~lcnt.. Thc eluate yields 0.21 g oE 13t-6~l-1-6(9~)-o~ide-11~,15R
dihydroxy-l6~sJR)-fluoro-l7-cyclollexyl-l8~l9J2o-trinor-prost-l3-enoic acid
nlcthyl cster, and 0.14 g of the 15S-epimer, m.p. ~3C - 84C (from ethyl
ether).
7~
~83i~
In the same way, reduction of the 6~H-isomer ~220 mg) yields 0.1 g
of 13t-6~H-6(9~)-oxide~ ,15R-dihydroxy-16~S,R)-fluoro-17-cyclohexyl-18,19,
20-trinor~prost-13-enoic acid methyl ester, m.p. 63 - 64 C (from isopropylic
ether), and 60 mg of 15S-alcohol.
Example 60
A solution of 0.15 g of 13t-6aH-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
NaH2PO4 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-6a}-1-6(9~)-oxide-11~,15R-di-
hydroxy-16-methyl-16-butoxy-18,19,20-trinor-prostenoic acid methyl ester (45
mg) and 15S-hydroxy-epimer (62 mg).
By reduction of 13t-5~H-5(9~)-oxide-11~-hydroxy-15-keto-16-methyl-
16-butoxy-18,19,20-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-5aH-5(9~)-oxide-11~-15R-dihydroxy-16-methyl-16-butoxy-1~,19,20--trinor-
prostenoi.c acid methyl ester, and 110 mg of 15S-epimer. These are then
saponifled to yielcl the corresponding free acids.
I`xample 62
Dropwise~ to a stirred 0.12 ~I solution of zincborohydride in ethyl
etller (~ ml) a sol~ltion of 0.135 g of 13t-5-bromo-6~ll-6(9~)-oxide-11~-hydroxy-
3~3~2
15-oxo-prostenoic acid methyl ester in 2 ml of anhydrous Et2O is added. The
mixture is stirred for 2 hours and the 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-pros~enoic acid methyl
ester and 46 mg of 15S-epimer were obtained.
Example 63
Starting from 13t-5,14-dibromo-6~H-6~9~)-oxide-11~-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-6~11-6~9~)-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-11~,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.~7 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 0.18 g of 15R-epimer. The 6~H-15S-alcohol epimer
is an oil with [~]D = + 12 ~hleOH).
Example 65
A solution in dry ethyl ether (20 ml) of 13t-16S-methyl-6~l-1-6~9~)-
oxide~ -hydroxy-15-oxo-prost-13-enoic acid methyl ester (0.002 ~vl, 0.72 g)
is added to a stirred etheral solution of zinc borohydride (0.01 hl, 100 ml).
The excess reagcnt is destroyed, after 30 - 45 minutcs, by addition of 2N-
~J~ ~
~33~42
sulphuric acid in NaCl saturated aqueous solution. TIle organic phase is
washed lmtil 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 ~, 0.27 g) of the 15R-hydroxy-isomer and
(1.1.10 4 M; 0.38 g) of the 15S-alcohol: 13t-16S-methyl-6~-6(9~)-oxide~
15S-dihydroxy-prost-13-enoic acid methyl ester. Using this procedure, the
~ollowing methyl esters were 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-11~,15S-dihydroxy-prost-13-enoic acid;
13t-6UH-S(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~ [~1D = ~21-7 ~ [~]365 = ~77 (C}IC13);
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-llx,15S-diIIydroxy-prost-13-enoic acid;
13t-5-iodo-6~H-6(9~)-oxide-16R-methyl~ ,15S-dihydroxy-prost-13-enoic acid;
13t-5-iodo-6~1-6(9cl)-oxide-16,16-dimethyl-llc~,,15S-dillydroxy-prost-13-enoic
acid;
13t-5-iodo-6~1I-6(9~)-oxide-11~15S-di]lydro~y-20-lIlethyl-prost-13-enoic acid,
[NJ - ~ 23, [~]365 ~ + 78 (CIIC13);
13t-5-chloro-6~II-6(9~)-oxide-16S-met}lyl-11~,15S-diIlydroxy-prost-13-enoic acid;
~31! 3~2
13t-5~1-1-5(9c~)-oxide-16S-methyl-llcY,15s-dihydroxy-prost-13-enoic acid;
13t-5~ 5~9~-oxide-16,16-dimethyl-11~,15S-dihydroxy-prost-13-enoic acid,
13t-4-bromo-5~H-5(9~)-oxide-16S-methyl-llc~,15S-dihydroxy-prost-13-enoic
acid;
13t-4-bromo-5~H-5(9~)-oxide-16R-methyl-llcY,15S-dihydroxy-prost-13 enoic
acid;
13t-4-bromo-5~H-5(9a)-oxide-16,16-dimethyl-llc~,15S-dihydroxy-prost-13-enoic
acid;
13t-4-iodo-5~H-5(9c~)-oxide-16S-methyl-llc~,15S-dihydroxy-prost-13-enoic acid;
lO 13t-4-chloro-5~H-5(9~)-oxide-16S-methyl-llc~,15S-dihydroxy-prost-13-enoic
acid;
13t-6~H-6(9CY) -oxide-16S-methyl-lla,15S-dihydroxy-14-bromo-prost-13-enoic
acid;
13t-6~H-6(9c~)-oxide-16R-methyl-llc/,15S-dihydroxy-14-bromo-prost-13-enoic
acid;
13t-6~H-6~9c~)-oxide-20-methyl-11~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-6~H-6(9c~)-oxide-15~S,R)-20-dimethyl-llc~,15S-dihydroxy-14-bromo-prost-13-
enoic acid;
13t-5~H-5~9c~)-oxide-16S-methyl-llu,15S-dihydroxy-14-bromo-prost-13-enoic
acid;
13t-5~H-5(9cY)-oxide-16R-methyl-llc~,15S-dihydroxy-14-bromo-prost-13-enoic
acid;
13t-5~}1-5~9c~)-oxide-20-methyl-llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-5~H-5~9c~)-oxide-16(S,R)-20-methyl -llci,15S-dihydroxy-l~l-bromo-prost-13-
enoic acid;
13t-5-l~rolllo-63l-l-6(')~)-oxide-16S-methyl-llc~,15S-diilydroxy-14-bromo-prost-13-
cnoic acicl;
13t-5-bromo-6~H-6(.9c~)-oxicle-16R-methyl~ ,15S-ciihydroxy-14-bromo-prost-13-
~3,~ _ ~_
~83~3~Z
enoic acid;
13t-5-bromo-6~H-6(9~)-oxide-20-methyl-11~,15S-dihydroxy-14-bro~o-pro~t 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-:Ll~,15S-dihydroxy-14-bromo-prost-13-
enoic acid;
13t-4-bromo-5~H-5(9~)-oxide-16R-methyl-:Lla,15S-dihydroxy-14-bromo-prost-13-
enoic acid;
13t-4-hromo-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-11~,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 chromatograp}lic separation.
Starting from 6~1 and 5~H diastereoisomeric 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 zinc borohydride in ethyl ether (25 ml). After 30 minutes,-the
excess reagent was destroyed by addition of a saturated solution of NaCl and
N 112S0~. After the usual work up the organic phase is separated and the crude
residue is chromatographed on SiO2 (eluent (CH2C12-etllyi ether) to yield
0.16 g of 13t-5-iodo-6~1-6(9~)-oxide-16R-methyl-15S-hydroxy-prost-13-enoic-
acid methyl ester ~md 0.095 g of 15R-epimer. Using this procedure the follow-
ing methyl esters were obtained:
12
13t-6~H-6~9cY)-oxide-15S-hydroxy-16S-methyl-prost-13-enoic acid;
13t-6~H-6~9c~i)-oxide-15S-~hydroxy-16R-methyl-prost-13-enoic acid;
13t-6~ll-6~9cri)-oxide-15S-hydroxy-16,16-dimethyl-prost-13-enoic acid;
13t-5~H-5~9cYi)-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-5~9cYi)-oxide-15S-hydroxy-16,16-dimethyl-prost-13-enoic acid;
13t-5-~romo-6~H-6~9cri)-oxide-15S-hydroxy-16S-methyl-pros-t-13-enoic acid;
13t-5-bromo-6~H-6(9cYi)-oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid;
13t-5-bromo-6~H-6~9cY.)-oxide-15S-hydroxy-16,16-dimethyl-prost-13-enoic acid;
13t-5-bromo-6~H-6(9cri)-oxide-15S-hydroxy-20-methyl-prost-13-enoic acid;
13t-5-bromo-6~H-6(9cYi)-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 6c~H and 5CYiH diastereoisomeric 15-keto compounds we prepare the
corresponding 15S- and 15R-alcohols.
Example 67
The following 15S-hydroxy-gcY,-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 5~ to 66;
13t-6~H-6(9cyi)-oxide-l1CYi~ 1 5S-dihydroxy-13-prostanoic acid;
13t-14-bromo-6~1-6(9c~)-oxide-11 CY; ~1 5S-dihydro~y-13-prostenoic acid;
13t-14-chloro-6~1-6(9a)-oxide-llcri,15S-dillydroxy-]3-prostenoic acid;
13t-5,14-dibromo-6~11-6(9cYi)-ox;.de-llcYi,15S-dillydroxy-l3-prostenoic acid;
13t 6~l-6(9~)-o~cide-llcYi,15S-dil-ydroxy-20-1netllyl-13-prostenoic acid;
13~-14-~romo-6~1-1-6(9cYi)-o~ide-llcYi,15S-dihydro~y-20-methyl-13-prostenoic acid;
13t-5,14-dibromo-6~1-6(9cYi)-oxide-llcYi,15S-clillydro~;y-20-methyl-13-prostenoic
acid;
3 ~:
~ .i
~1~31!39~
13t-5-iodo-6~H-6~9a)-oxide-lla~l5s-dihydroxy~2o-nlethyl-l3-prostenoic acid;
13t-5-iodo-14-bromo-6~H-6(9~)-oxide-11 ,15S-dihydroxy-20-methyi-13-prostenoic
acid;
13t-14-bromo-6~H-6(9a)-oxide~ ,15S-dihydroxy-16~S,R)-fluoro-17-cyclohexyl-
18~19J20-trinor-prost-13-enoic acld;
13t-5,14-dibromo-6~-6(9a)-oxide-lla,15S-dihydroxy-16(S,R)-fluoro-17-cyclo-
hexyl-18,19,20-trinor-prost-13-enoic acid;
13t-5-bromo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16(S,R)-fluoro 17-cyclohexyl-
18jl9~20-trinor-prost~13-enoic acid;
13t-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-difluoro-17-cyclohexyl-18,19,20-
trinor-prost-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-lla~15S-dihydroxy-16(S,R)-fluoro-17-phenyl-18,19,20-
trinor-prost-13-enoic acid;
13t-14-bromo-6~H-6(9)-oxide-lla,15S-dihydroxy-16(SJR)-fluoro-17-phenyl-18,
19,20-trinor-prost-13-enoic acid;
13t-6BH-6(9a)-oxide-lla,15S-dihydroxy-17-cyclopentyl-18,19,20-trinor-prost-
13-enoic acid;
13t-6~H-6(9a)-oxide-lla,15S-dihydroxy-17-cyclohexyl-18,1g,20-trinor-prost-
13-enoic acid;
13t-14-bromo-6~H-6t9a) -oxide-lla,15S-dihydroxy-17-cyclohexyl-18,19J20_trinor-
prost-13-enoic acid;
13t-SJ14-dibromo-h~1-6(9a)-oxide-~ Jl5S-dihydroxy-l7-cyclohexyl-l8~l9~2
trinor-prost-13-enoic acid;
,~"
13t-5-~romo-6~H 6(9~)~oxide~ ,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-
prost-13-enoic acid;
13t-5-chloro-6~H-6(9a)-oxide-11~,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-
prost-13-enoic acid;
13t-5-iodo-6~H-6(9~)-oxide-11,15S-dihydroxy-16-methyl-16-butoxy-18,1g,20-
trinor-prost-13-enoic acid;
13t-5-iodo-6~H-6(9a)-oxide-ll~,lSS-dihydroxy-16~methyl-16-propoxy-18,19,20-
trinor-prost-13-enoic acid;
13t-5-iodo-6~H-6C9a)-oxide-lla,15S-dihydroxy-16-methyl-16-amyloxy-18,19,20-
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-6C9a)-oxide lla,15S-dihydroxy-16-~p-fluoro)-phenoxy-17,18,19,20-
tetranor-13-prostenoic acid;
13t-6~H-6~9)-oxide-lla,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-
prostenoic acid;
13t-6~H-6~9)-oxide-lla,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-
13-prostenoic acid;
13t-6~H-6t9~)-oxide-lla,15S-dihydroxy-16-~m-chloro)-phenoxy-17,18,19,20-
tetranor-13-prostenoic acid;
13t-6~H-6(9a)-oxide-11~,15S-dihydroxy-16-~m-trifluoromethyl)-phenoxy-17,18,
19,20-tetranor-13-prostenoic acid;
13t-14-bromo-6~H-6~9)-oxide-11,15S-dihydroxy-16-~p-fluoro3-phenoxy-17,18,
19,20-tetranor-13-prostenoic acid;
13t-14.bro~o~6~-6~9~-oxide~ll,lSS-dihydroxy-16 phenoxy~17,18,19,20-tetranor-
13-prostenoic acid;
13t-14-bromo-6~H~6~9) -oxide-ll,lSS-dihydroxy-16-~m-chloro)-phenoxy-17,18,
19 J 20-tetranor-13.prostenoic acid;
'~ ~ O ~
~31!3~
13t-14-bromo-6~H-6~9a).oxide-lla,lSS-dihydroxy~16~(m-trifluoromethyl)-phenoxy-
17,18,19,20-tetranor-13-pros~enoic acid;
13t-5-iodo-6~H-6(9~)-oxide-11,15S-dihydroxy-16-(p-~l~oro)-phenoxy-17,18,19,
20-tetranor-13-prostenoic acid;
13t-5-iodo-6~H-6~9a) -oxide-lla,15S-dihydToxy-].6-phenoxy-17,18,19,20-tetranor-
13-prostenoic acid;
13t-5-iodo-6~H-6~9a)-oxide-11~,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-
tetranor-13-prostenoic acid;
13t-5-iodo-6~H-6~9a)-oxide-lla,15S-dihydroxy-16-Cm-chloro)-phenoxy-17,18,19,
20-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~ 15S-dihydroxy-13-pros~enoic acid;
13t-14-bromo-5~H-5~9a)-oxide-lla,15S-dihydroxy-13-prostenoic acid;
13t-14-chloro-5~H-5(9a)-oxide-lla,15S-dihydroxy-13-prostenoic acid;
13t-4,14-dibromo-5~H-5(9~)-oxide~ ,15S-dihydroxy-13-prostenoic acid;
13t-5~H-5(9a)-oxide-lla,15S-dihydroxy-20-methyl-13-prostenoic acid;
13t-14-bromo-5~H-5(9a)-oxide-lla,15S-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(9~)-oxide-lla,15S-dihydroxy-20-methyl-13-pros~enoic acid;
13t-4-iodo-14-bromo-5~H-5(9a)-oxide-lla,15S-dihydroxy-20-methyl-13-prostenoic
acid;
13t-14-bromo-5~H-5(9aj-oxide-lla,15S-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-
18,19,20-trinor-prost-13-enoic acid;
13t-4,14-dibromo-5~H~5~9a)-oxide-lla,15S-dihydroxy-16~S,R)-fluoro-17-cyclo-
hexyl~l8,19,20~trinor~prost-13-0noic acid;
13t-4-bromo-5~H-5t~a)-oxide-lla,15S-dihydroxy-16(S,R)-fluoro-17-cycloh0xyl-
i~3 ~
,9
3~3~2
18,19,20-trinor-prost_13_enoic acid;
13t-5~H-5(9a3-oxide-11,15S-dihydroxy-16~S,R)-fluoro-17-phenyl-18,19,20-
trinor-prost-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-5~H-5(9a)-oxide-lla,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-pros~-
13-enoic acid;
lQ 13t-14-bromo-5~H-5C9a)-oxide-lla,15S-dihydroxy-17-cyclohexyl-18,19,20-
trinor-prost-13-enoic acid;
13t-4,14-dibromo-5i~H-5C9a)-oxide-lla915S-dihydroxy-17-cyclohexyl-18,19320-
trinor-prost-13-enoic acid;
13t-5~H-5C9a)-oxide-lla,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13^
prostenoic acid;
13t-4-iodo-5~H-5~9a)~oxide-lla,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-
13-prostenoic acid;
13t-4-iodo-5~-5(9a)-oxide-lla,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-
tetranor-13-prostenoic acid;
13t-4-iodo-5~H-5C9a)-oxide-lla,15S-dihydroxy-16(m-chloro)-phenoxy-17,18,19,
20-tetranor 13-prostenoic acid;
13t-4-iodo-5 ~1-5C9a)-oxide-lla,15S-dihydroxy-16-~m-trifluoromethyl)-phenoxy-
17,18,19,20-tetranor~13-prostenoic acid.
In similar way, we prepare the diastereoisomeric ~l-9a-oxide-15S-
and ~I-9a-oxide-lSR-alcohols when we use aH-9a-oxide-15-~eto diastereoisomer
~s startin~ matericLl~
~11 these~ esters are then saponified to obtain the free acids.
_ ,~
i3~3~2
Example 68
0.46 g of 13t-5~ll-5(9c~)-oxide-16S-methyl-ll~-hydroxy-15-oxo-prost-
13-enoic acid methyl ester are treated with pyridine (2 ml) and acetic an-
hydride ~l ml). After 6 hours at room temperature the mixture is diluted with
brine, acidified to 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 (~ eOH = 229 m~, ~ = 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 decomposed with a N solution of H2S04
and after the usual work -up, 0.47 g of 13t-5~H-5~9c~)-oxide-16S-methyl-llc~,
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 -5 C, -10 C, is
treated with a solution of BF3 etherate (1.2 x 10 4 M) in Cl-l2C12 and then with
a 5% solution of diazomethane in C~12C12 until a persistent yellow coloration.
The reaction mixture is evaporated to half volume under vacuum, washed with a
5% aqueous NaHCO3 solution and water to neutral, and evaporated to dryness to
yield 0.47 g of 13t-5~H-5(9c~)-oxide-16S-methyl-llc~ ydroxy-15(SJR)-melhoxy-
prost-13-enoic acid-ll-acetate wllich is separated in the individual isomers
by chromatography on SiO2 using benzene-ethyl ether (S5:15) 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 NaLI2P0~, the methanol evaporated uncler vacuum and the residue is
extracted ~Yith etl-yl ether (2 x 5) ethyl acetatc (2 x 6 ml). The combincd
organic phases are evaporated to dryness to yielcl 180 mg of the crude 13t-
5~ll-5(Jc~)-ox:icie-16S-methyl-llcY-IIydroxy-15(S,R)-methoxy-prostenoic acid methyl
estcr, whicll is then readily scparated by means of a silica gel column chroma-
tography using C~l2Cl2-cthyl ether 80:20 as eluent to yield the two pure
t ~ ~ ~
~3l!3~;2
isomers: 15S-methoxy and 15R-methoxy. Using the same procedure the following
methyl esters were obtained:
13t-6~1-6(9~)-oxide-16S-methyl~ -hydroxy-15S-methoxy-prost-13-enoic acid;
13t-6~H-6(9~)-oxide-16R-methyl-ll~-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-6~H-6(9~)-oxide-20-methyl-11~-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9~)-oxide-20-methyl-11~-hydro~-15S-methoxy-prost-13-enoic
acid;
13t-5-bromo-6~H-6(9~-oxide-11~-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9~-oxide-16S-methyl-lla-hydroxy-15S-methoxy-prost-13-enoic
acid,
and thelr epimeric 15R-methoxy compounds are obtained s~arting from the cor-
responding ll-acetoxy-15-keto compounds.
Using in this procedure the~H-diastereoisomer instead of the ~H,
the corresponding ~H-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
of diazomethane.
Example 69
To a solution of 0.26 g of 13t-6~ 6(9~)-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 o 13t-6~H-6(9~)-oxide-
15S-ethoxy-]6S-methyl--prostenoic acid methylcster, and 0.1 g of 15R-ethoxy
isomer.
~heZl a mixture of 15S,15R-alcohols, for example 13t-6~H-6(9~)-oxide-
3~2
ll~,l5(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 after chromatographic separation the 13t-6~
6(9cY)-oxide-llcY,15S-dimethoxy-16S-methyl-prostenoic acid methyl ester beside
the 15R-epimeric derivative.
In a similar way the following 15S-alkoxy prostenoic derivatives
were obtained:
13t-5~H-5(9~)-oxide-llcY,15S-dimethoxy-prostenoic acid;
13t-6~H-6(9cY)-oxide-llcY,15S dimethoxy-prostenoic acid;
13t-6~H-6(9cY)-oxide-5-bromo-llcY,15S-dimethoxy-prostenoic acid;
13t-6~H-6(9cY)-oxide-5-iodo-llcY,15S-dimethoxy-prostenoic acid;
13t-5~1-1-5(9cY)-oxide-15S-me~hoxy-16S-methyl-prostenoic acid;
13t-6~H-6(9cY)-oxide-15S-methoxy-16S-methyl-prostenoic acid;
13t-6~H-6(9cY)-oxide-15S-methoxy-16R-methyl-prostenoic acid;
13t-6~H-6(9cY)-oxide-15S-methoxy-16-methyl-16-butoxy-1~,19,20-trinor-
prostanoic acid,
and their 15R epimers are obtained and when they are saponified with LiOH in
methanol the free acids are prepared. The same procedure can be used to ob-
tain diastereoisomeric ~H-9cY-oxide derivatives.
Example 70
To a stirred solution of 1.33 g of 13t-6cYH-6(9cy)-oxide-11~-hydroxy_
15-oxo-prost-13-enoic acid methyl ester-ll-acetate in 6 ml of toluene and 54
ml of benzene, cooled at ~4 C, a solution of 1.67 g of methylmagnesium iodide
in ethyl ether is added. After 20 minutes, the excess reagent is decomposed
Wit}l an icecl 20~ solution of ammonium chloride in water. After dilution with
one vol~mle of ethyl ether ~he organic phase is ~aslled with water, sodium bi-
carbonate and IYater) dried over magnesium sulpllate, treated with 0.1 ml of
3i~Z
pyridine and evaporated to dryness to yield 1.2 g of 13t-6oH-6(9~)-oxide-llo,
15(SIR)-dihydroxy-15-methyl-prostenoic acid-methylester-ll-acetate, of 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 the two
alcohols is dissolved in anhydrous methanol (20 ml) and stirred for 4 hours
with 0.25 g of K2CO3. The mixture is evaporated to dryness, the residue is
partitioned between ethyl ether and aqueous 15% NaH2P0~. 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-6OH-one
6(9O)-oxide-11O,15R-dihydroxy-15-methyl-prost-13-enoic acid methyl ester,
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 0.14 g
of 13t-6O!-1-6(9O)-oxide-11O,15S-dihydroxy-15-methyl-prost-13-enoic acid. The
corresponding 6~H-isomers are prepared in the same way.
Example 71
To 1.79 g of 13t-5OH-5(9O)-oxide-llo-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 NH~Cl solution, concentrate the organic phase under vacuum, and
take up with ethyl ether to yield 1.62 g of 13t-5OH-5(9O)-oxide-11O,15(S,R)-
dihydroxy-15-ethynyl-prost-13-enoic acid methyl ester-ll-acetate, which is
dissolved in anhydrous methanol and trcated witll 250 mg of anhydrous potassium
carbonate for 3 hours under shaking. Evaporated under vacuum and dilute witl
20o aqueous Nall2~0~l and ethyl ether. After evaporating the solvent, the
o~ganic phase yields 1.~1 g of l~t-5OI-l-5~9O)-oxide-11O,15~S,R)-dihydroxy-15-
`' 9~
3~
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(9~)-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 - 5C and let stand for 4 hours at room temperature. Decompose the excess
reagent ~ith 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 wi~h methylene chloride-etllyl ether to yield
0.41 g of 13t-5-bromo-6~H-6(9~)-oxide-15R-hydroxy-15-vinyl-prostenoic acid
methyl ester, and 0.62 g of 15S-isomer, which after saponification ~ith 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 of 0.98 g of 13t-5-bromo-6~H-6(9~)-o~ide-11~-hydroxy-15-
oxo-20-methyl-prostenoic acid methyl ester-ll-acetate in 30 ml of benzene-
toluene ~85:15) is cooled at 3 - 4 C and to tl-is 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 ~i-th an iced
solution oE 15% Nl-14Cl, wash the organic phase repeatedly with water to neutral
tllen evaporate. 'I`he crude 15-phenyl-15(S,R)-llydroxy delivative is clissolved
in anhy(lrous metllanol to wllich 0.25 g. of ~2CO3 is added, kept shaking for
2 hours. Evaporate to dryness, dilute with aqueous 20% NaH2PO4 and ethyl
cther, and from tho organic pl-ase after evaporation of the solvent, there is
~L~83~3~2
a yield of 0.81 g of 13t-5-bromo-6~H-6~9c~)-oxide-llci,15(S,R)-dihydroxy-15-
phenyl-20-methyl-prostenoic acid methyl ester, which after separation on
silica gel with ethyl ether elution yields 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 magnesi~n, ~orking to one of the procedures
given in example 70 to 73, ~he following methylesters were prepared:
13t-6~H-6~9c~)-oxide-15S-hydroxy-15-methyl-prostenoic acid;
13t-6~H-6(9ci)-oxide-15S-hydroxy-15,20-dimethyl-prostenoic acid;
13t-6~H-6(9cl)-oxide-15S-hydroxy-15-ethyl-prostenoic acid;
13t-6~H-6(9cY)-oxide-15S-hydroxy-15-ethynyl-prostenoic acid;
13t-6~H-6(9c~)-oxide-11~,15S-dihydroxy-15-methyl-prostenoic acid;
13t-6~H-6(9cY)-oxide-llc~,15S-dihydroxy-15-ethyl-prostenoic acid;
13t-6~H-6(9~)-oxide-llc~,15S-dihydroxy-15-vinyl-prostenoic acid;
13t-6~H-6(9~)-oxide-llc~,15S-dihydroxy-15-ethynyl-prostenoic acid;
13t-6~H-6(9~)-oxide-11~,15S-dihydroxy-15-phenyl-prostenoic acid;
13t-6~H-6(9c~)-oxide-llc~,15S-dihydroxy-15,20-dimethyl-prostenoic acid;
13t-5-bromo-6~H-6(9cY)-oxide-llcY,15S-dihydroxy-15-methyl-prostenoic acid;
13t-5-bromo-6~H-6(9c~)-oxide-llc~,15S-dihydroxy-15-vinyl-prostenoic acid;
13t-5-bromo-6~H-6~9~)-oxide-llc~,15S-dihydroxy-15-ethynyl-prostenoic acid;
13t-5-bromo~6~H-6(9a)-oxide-11~,15S-dihydroXy-15-ethyl-prostenoic acid;
13t-5-bromo-6~H-6~9c~)-oxide-11~,15S-dihydroXy-15-phenyl-prosteTIoic acid;
13t-4-bromo-5~ll-5~9c~)-oxide-llca,15S-dihydroxy-15-methyl-prostenoic acid;
13t-4-bromo-5~1l-5~9~)-oxide-11~,15S-dihydroxy-15,20-climethyl-prostenoic acid;
13t-4-bromo-5~l-1-5~9c~)-oxide-11~,15S-dillydroxy-15-ethynyl-prostenoic acid;
13t-5~1-5~9c~)-oxlde-llc~,15S-dillydroxy-15-methyl-prostenoic acid;
13t-5~l-5~9c~)-oxidl3-llc~,15S-dillydroxy-15,20-di!nethyl-prostenoic acid;
~S,
~ ~:r~ ~~
:~83~
13t-5~1-5~9ct)-oxide-11~,15S-dihydroxy-15-phenyl-prostenoic acid;
13-t-5 ~1-5~9~)-oxide-11~,15S--dihydroxy-15-ethynyl-prostenoic acid;
13t-5~H-5~9~)-oxide-llct,15S-dihydroxy-15-vinyl-prostenoic acid;
13t-5~H-5~9~)-oxide-11~,15S-dihydroxy-15-methyl-prostenoic acid,
and their 15R-hydroxy epimers.
Analogously starting from the ct~-~9~)-oxide-15-keto-compounds ~e
obtained the corresponding ~H-~9~)-oxide-15-substituted alcohols.
Example 75
To a solution of 0.5 g of 13t--6~H-6~9ct)-oxide-llct,15S-dihydroxy-
14-~romo-16S-methyl-prostenoic acid-methyl ester-ll-acetate in 2 ml of di-
methylformamide, dimethyl-t-butyl silane chloride ~0.21 g) and trietllylamine
(0.16 g) are added. Keep sha~ing for 2 hours, then dilute l~ith 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 ~ith
cyclohexane-ethyl ether 90:10 eluent, yields 0.57 g of 13t-6~1-6~9~)-oxide
11~,15S-dihydroxy-14-bromo-16S-methyl-prostenoic acid methyl ester-ll-acetate-
15-dimethyl-t.butylsilylether, from ~hich, by transesterification in anhydrous
methanol and 0.5 molar equivalents of K2C03, the corresponding ll-hydroxy-
derivative is yielded.
Example 76
To 0.52 g of 13t-5,14-dibromo-6~H-6~9ct)-oxide-11~,15S-diilydroxy-
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 wasll with a 5O solutioll of KIIC03 and water to neutral,
and evaporate to dryness. Filter througll silica gel ~ith cyclohexane-ethyl
ether 90:10 as elllent, ~hich yields 0.59 g of 13t-5,14-dil)romo-6~ll-6~9~)-oxide-
llct,15S-dihydroxy-prostenoic acid methyl ester-11,15-bis-tetrahydropyranyl-
ethcr .
~3~
Example 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 the corresponding silyloxy or the corres-
ponding acetalic ethers.
Example 78
Under an atmosphere of inert gas, to a stirred solution of 0.46 g
of 13t-14-bromo-6~H-6(9c~)-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 until neutral and evaporated to dryness to
give 30 mg of 6~H-6(9c~)-oxide-l5s-methoxy-l6s-methyl-prost-l3-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
dimethylsulfoxide solution o 0.445 g of 13t-5~1-5~9~)-oxide-14-bromo-16R-
methyl-prost-13-cnoic acid. St;irring is continued ~or 30 minutes and then a
solu-tion of 0.19 g of K--tert-butylate is addecl. After 30 minutes stirring,
the mixture is diluted with 3 volumes of water and stirred for 2 more hours.
~Eter acidiEiccltiotl to pl-l 5.2, it is extracted with ethyl ether:hexane 80:20
and tlle organi.c ext:racts are dried and evaporated to dryness to give 0.31 g
I ~ ' -~
~31~4~Z
of 5~ 5~9~)-oxide-16R-methyl-prost-l3-ynoic acid.
Example 80
To a solution of sodium methylsulfinylcarbanion, obtained by heating
at 60C 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-11~,15S-
dimethoxy-14-bromo-16~S,R)-fluoro-20-methyl-prost-13-enoic acid methyl ester
~0.86 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.
Exam~le 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(9cY)-oxide-11~,15S-dihydroxy-16-
m-trifluoromethylphenoxy-l7~l8~l9~2o-tetranor-prost-l3-enoic acid-11,15-
bis-tetrahydropyranyl-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 to pll 4.5 and extracted
with eth~l ether to give 0.54 g of 5cY~-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 NallC03, evaporatcd under vacuum and the residue partitioned
be~cen ~ater and ethyl ether. The organic phase is evaporated and after
passing the residue through silica gel 0.1 g of 5~11-5(9~)-oxide-11~,15S-
clil~ydroxy-16-m-trifluorolllethylphenoxy-17,18,19,20-tctranor-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 wi~h 3.5 ml of 0.2N oxalic
acid for 8 hours at 40C, after evaporation of the acetone under vacuum, ex-
traction of the aqueous phase with ethyl ether and chromatography on sillca
gel with ethyl ether:etllyl acetate 95:5 the free acid (95 mg) is obtained.
In the same way, starting from 13t-14-chloro-6~H-6(9~)-oxide-11~,
15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid-11,15-bis-
dioxanylether the 6~H-6(9~)-oxide-11~,15S-dihydroxy-17-cyclohexyl-18,19,20-
trinor-prost-13-ynoic acid is obtained.
Example 82
To a solution of 0.48 g of l3t-14-bromo-6~H-6(9~-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 65C. 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 ben~ene-ethyl ether 80:20), 6~H-6(9~)-oxide-11~,15S-dihydroxy-
16-cyclohexyloxy-17,18719,20-tetranor-prost-13-ynoic acid methyl ester (0.29
g) is obtained.
Exam~le 83
Using one of the procedures described in examples 78 to 82 and
`starting from the corresponding 13t-14-halo-prost-13-enoic acids, the follow-
ing prost-13-ynoic acids are prepared:
6~ll-6(9~)-oxide-11~,15S-dihydroxy-prost-13-ynoic acid;
6~ 6~9~)-oxide-11~,15R-dihydroxy-prost-13-ynoic acid;
6~ 6~9~)-oxide-15-methoxy-prost-13-ynoic acid;
6~H-6(9~)-oxide-11~,15S-dihydroxy~16S-methyl-prost-13-ynoic acid;
~83l34!~
6~H-6~9~)-oxide-11~,15S-dihydroxy-16S,20-dimet}lyl-prost-13-ynoic acid;
6~H-6(9~)-oxide-11~,15S-dihydroxy-16R-methyl-prost-13-ynoic acid;
6~H-6(9~)-oxide~ ,15S-dihydroxy-l~S-fluoro-prost-13-ynoic acid;
6~H-6(9~-oxide-11~,15S-dihydroxy-16,16-difluoro-prost-13-ynoic acid;
6~H-6(g~)-oxide-llci,15S-dihydroxy 20-methyl-prost-13-ynoic acid;
6~H-6~9~)-oxide-11~,15S-dihydro~y-17-cyclohexyl-18,19,20-trinor-prost-13-
ynoic acid;
6~H-6~9c~)-oxide-lla,15S-dihydroxy-16-fluoro-17-cyclohexyl-18,19,20-trinor-
prost-13-ynoic acid;
6~H-6~9~)-oxide-11~,15S-dihydroxy-16-p-fluorophenoxy-17,18,19,20-tetranor-
prost-13-ynoic acid;
6~H-6~gc~)-oxide-llci,15S-dihydroxy-17-phenyl-18,19,20-trinor-prost-13-ynoic
acid;
5~H-5~9~)-oxide-llc~,15S-dihydroxy-16S-methyl-prost-13-ynoic acid;
5~H-5~9a)-oxide-11~,15S-dihydro,cy-16S,20-dimethyl-prost-13-ynoic acid;
5~H-5~9ci)-oxide-llc~,15S-dihydroxy-16R-methyl-prost-13-ynoic acid;
5~H-5(9~)-oxide-11~,15S-dihydroxy-16S-fluoro-prost-13-ynoic acid;
5~H-5~9a)-oxide-lla,lSS-dihydroxy-prost-13-ynoic acid;
5~H-~5~9~)-oxide-llcL,15S-dihydroxy-20-methyl-prost-13-ynoic acid.
Starting from ciH-~9ci)-oxide compounds and using the same procedure,
the epimeric ciH-(9~)-oxide-13-ynoic compounds are prepared.
Example 84
. .
A solution of 0.35 g of mercuric acetate in methanol is added at
room temperature, with stirring, to a solution of 0.54 g of 5c,13t-9c~ ,15S-
trihydro~y-prostadienoic acid methyl ester-11,15-bis-THP-ether ~PGE2 -bis-
Tf-lP-ether-methyl ester). ~fter stirring for 15 mintltes, 50 mg of sodium
borohyc1rlde is added in small yortions, the elemental mercury generated is
removed by filtration and the methanol is evaporated under vacuum. The resi-
due is partitioned between dichloromethane/~ater; the organic phase, after
3~
washing with sodium bicarbonate and water until neutral, is evaporated to
give 0.51 g of crude 13t~ ,15S-dihydroxy-6~H-6(9tx)-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 extTacted
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(9N)-oxide-prostenoic
acid methyl ester ~0.11 g; m.p. 67 - 69C) is obtained. Then, after a mixture
of diastereoisomers as 5 - 10% of ethyl acetate is added to ethyl ether, 13t-
llN,15S-dihydroxy-6~H-6(9N)-oxide-prostenoic acid methyl ester (0.16 g;
[N]D = + 19.62 (C~IC13)) is collected.
A sample of the later compound, after crystallization, shows m.p.
40 - 41C~ [N]D = +25-2 ~ ~]365 = +83.8 (CI-IC13).
The crude free acid has [N]D = +18.3 (EtOII).
A sample is crystallized from pentane-ethyl ether affording pure
crystalline 13t-6~H-6(9~)-oxide-llN,15S-dihydroxy-prost-13-enoic acid, m.p.
80 - 81 C, [N]D = +32.5 , [N]3650 = +111.6 (EtO~I). The mass spectrum of the
compound shows the following peaks (m/e, intensity, structure):
336 7% [M-H20] , 318 3% [M-2H20] ; 292 100~ [~ I20-44] ;
264 30% [M-H20-C~I2CHC02I-I] ; 235 4% [M-~I20--(CI-I2)4C02~I].
The mass spectrum of the 6NI-I-diastereoisomer is substantially
similar.
Example 85
~ solution of 0.19 g of 5c,13t-9~,11N,15S-triIIydro~y-15-metIlyl-
PG~2N-methyl ester in 2.5 ml of THF is added to 0.3 g of mercuric acetate in
1.5 ml ~ater/3.0 ml THF. ~ter 30 minutcs of stirring, 60 mg of sodium
~38~
borohydride in 1.2 ml of water is added to the deep yellow suspension. After
the mercury is separated, the TIIF is removed under vacuum 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 purified by thin layer chromatography to give 0.04 g of 13t~ ,15S-di-
hydroxy-6~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 ~C}IC13).
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 reac~ed 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~ 6~9~)-oxide-5-bromomercuric prostenoic acid methyl
ester, from whlch 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 6~1-6(9~)-oxide diastereoisomers.
Example 87
A solution of 0.55 g of 5c-9~ ,15S-trihydroxy-prostenoic acid
methyl ester in 2.5 ml of D~IE is added to a solution of 0.5 g of mercuric
acetate in 2 ml of water/ 4 ml of D~IE. 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 D~IE is removed under vacuum, and the residue
is extracted several times with dichloromethane. The organic phase is evap-
orated to dryncss, adsorbed on silica gel and eluted with ethyl ether/cthyl
acetate to give 0.21 g of 11~,15S-dihydroxy-6~H-6(9~)-oxide-prostenoic acid
me~hyl ester and 0.18 g of the 6~II-6~9~)~oxide isomer.
_ ~_
~L83~Z
Example 88
A solution of 116 mg of 5c-9~ ,15S-trlhydroxy-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 ~ater/ethyl acetate. Evaporation of the organic phase to dryness affords
crude llcY,15S-dihydroxy-6~H-6(9~)-oxide-17-cyclohexyl-20,19,18-trinor-prost-
13-ynoic acid methyl ester-11,15-bis-THP-ether ~lO0 mg); this is treated in
acetone (4 ml) with 2.5 ml of 0.2N oxalic acid overnight at 40C. After rc-
moval of the acetone under vacuum, the mixture is extracted with ethyl acetate.
Evaporation of solvent gives a residue ~hich is purified 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(9cY)-oxide-isomer, [~]D = ~ 26.5,
[~]365 ~ + 84 ~EtOH); M 406, M-H2O 388.
Under the same conditions, 5c-9~,11cY,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(9CY)-
oxide isomer.
Example 89
0.24 g of 13t-11~,15S-dihydroxy-6~H,6(9~)-oxide-16-methyl-16-butoxy-
2Q,19,18-trinor-prostenoic acid methyl ester and 0.13 g of the 6~11-6(9cY)-oxide
isomer are obtainad from the reaction of 1.01 molar equivalent of mercuric
acetate ~636 mg) in 10 ml o methanol and 1.1 g of 5c,13t-9cY,11~,15S-trihy-
droxy-16-methyl-16-butoxy-20,19,18-trinor-prostadienoic acid methyl ester-ll,
15-bis-TIlP-ether in 5 ml oE methanol~ The mercury compound so prepared is
rcclucecl in situ by tl~e cautious adclition of 85 mg of sodi~lm borohvdride in
'`' /.f~
, ~
~33~
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 of
acetone are added, and the resulting mixture is held at 50C for 12 hours.
The organic solvents are removed under vacuum, and the resulting solution is
saturated ~ith sodium sulfate and extracted with ethyl acetate. The organic
phase is washed with 30% a~nonium sulfate (2 x 5 ml) and 2.5 ml of water;
after drying over NaS04, it is evaporated to give a crude residue whicn is
purified on silica gel using an eluent containing an increasing ~raction of
benzene-methyl acetate, to give the isomeric 6aH-6~9a)-oxide and 6~H-6(9a)-
oxide.
From the above reaction with 16-_-chloro-phenoxy,16-~-fluoro-
phenoxy, and 16-m-trifluoromethyl-phenoxy-5c,13t-9~,lla,15S-triIlydroxy-20,
19,18,17-tetranor-prost-5,13-dienoic acid methyl ester-11,15-bis-TllP-ether
and the analogous 17-phenyl-18,19,20-trinor-derivative were obtained respec-
tively:
13t-lla,15S-dihydroxy-6~H-6(9a)-oxide-17-phenyl-20,19,18-trinor-prostenoic
acid methyl ester, [a]D = ~ 28 ;
13t~ ,15S-dihydroxy-6~H-6(9a)-oxide-16-m-chloro-phenoxy-20,19,18,17-tetranor-
prostenoic acid methyl ester, [~]D = + 31 ;
13t-lla,15S-dihydroxy-6~H-6(9~)-oxide-16-p-fluoro-phenoxy-20,19,18,17-tetranor-
prostenoic acid methyl ester, [~]D = ~ 30C;
13t-lla,15S-dihydroxy-6~H-6(9a)-oxide-16-m-trifluoromethyl-pheno~y-20,19,18,
17-tetranor-prosteno;c acid methyl ester, ~]D = ~ 33;
and their 6aI-I-6(9~)-oxide isomers whicIl show ~a]D rallging between ~8 and
12 in CI-IC13.
~xalllplc 90
_.
Using tl~e 16S-fluoro-17-cyclohexyl-5c,13t-9~,11a,15S-tri}lydroxy-
20,19,1~-trinor-prosta-5,13-dienoic acid methyl ester-11,15-bis-THP-ether, in
o~
33~2
the procedure of example 89, the 13t-lla,15S-dihydroxy-6aH-6(9)-oxide-16S-
fluoro-17-cyclohexyl-20~19,18-trinor-prost-13_enoic acid methyl ester,
and its 6~H-6(9~)-oxide diastereoisomer are o~tained.
Example 91
0,12 g of 13t-lla,15S-dihydroxy-6~H-6~9a)-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 hours, the methanol is removed under vacuum.
The residue is diluted with water (2 ml~ and extracted with ethyl ether to
remove neutral impurities. The alkaline aqueous phase is acidified by treat-
ment with 4 ml of 30% aqueous NaH2PO4 and extracted several times with ethyl
ether. The later combined ether extracts are washed with water ~ x 1 ml) and
dried; removal of the solvent affords 91 mg of 13t-11,15S-dihydroxy-6~H-6(9a)-
oxide-prost-13-enoic acid, m.p. 78 - 80C, [a]D = ~ 31 (EtO~I). This procedure
is used for saponiflcation of the esters from the preceding examples to the
corresponding free acids.
Example 92
lla,15S-dihydroxy-6~H-6(9a)-oxide-16S-methyl-prost-13-ynoic acid
C0.11 g) in methylene chloride is treated with 1.5 molar equivalent of di-
azomethane in methylene chloride. After 15 minutes, solvent is removed under
vacuum and the residue adsorbed on silica gel. Elution with ethyl ether/
benzene ~70:30) gives, in the following order, 12 mg of lla-hydroxy-15S-
methoxy-6~H-6(9~)-oxide-16S-methyl-prost-13-ynoic acid methyl ester and 78 mg
of lla,155-dihydroxy-6~H-6(9a) oxide-16S-meth~l-prost-13-ynoic acid methyl
ester. Using in this procedure diazoethane instead of the diaæomethane, lla-
hydroxy-15S-ethoxy-6~1-6(9a)-oxide-16S-methyl-prost-13-ynoic acid ethyl ester
is obtained.
S-
38~
Exam~
A solution of 12 (0-33 g) in methylene chloride is added to a sus-
pension of finely divided calcium carbonate in 6 ml of 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 ester). 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 *he 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
~9~)-oxide-lla,15S-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 wasned 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 o~ 13t-5-iodo-6~H-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~,
1 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 acid3
[~D = ~ 23 ~ [~]365 = ~ 78 ~CHC13);
13t^5-iodo-6SH-6(9~)-oxide-11~,15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-
prost-13-enoic acid;
13t-5-iodo-61-l-6~9~)-oxide-11~,15S-dihydroxy-lS,19,20-trinor-17-cyclohexyl-
prost-13-enoic ~cid;
~6
-"I,k~-
3313~
13t-5-iodo-6~1-6(9cY)-oxide-llc~,15S-dihydroxy-18,19,20-trinor-17-phenoxy-prost-13-enoic acid;
13t-5-iodo-6c~1-6(9cx)-oxide-llc~,15S-dihydroxy-18,19,20-trinor-17-phenoxy-prost-
13-enoic acid;
13t-5-iodo-6~H-6~9~)-oxide-15S-hydroxy-prost-13-enoic acid;
13t-5-iodo-6~H-6(9c~)-oxide-lSS-hydroxy-prost-13-enoic acid;
13t-5-iodo-6~1-6(9ci)-oxide-llc~,lSS-dihydroxy-prost-13-ynoic acid;
13t-5-iodo-6c~-6(9c~)-oxide-llc~,lSS-dihydroxy-prost-13-ynoic acid;
5-iodo-6~H-6(9c~-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-ynoic acid;
5-iodo-6~H-6(9c~)-oxide-20-methyl-llc~,15S-dihydroxy-prost-13-ynoic acid,
[C~]D = ~ 20 (CHC13).
Example 94
To a solution o 0.22 g of 5c,13t-9c~,11c~,15S-trihydroxy-15-methyl-
PGF2 -methyl ester in 10 ml of CH2C12 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 with 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-llc~,15S-di-
hydroxy-prost-13-enoic acid methyl ester and 0.021 g of the isomeric 5-iodo-
6c~H-6(9c~)-oxide are obtained.
Example 9S
0.288 g of 5c-l6~l6-dimethyl-9ci~llc~l5s-trihydroxy-prost-5-enoic
acid methyl ester in a solution of 60 mg of pyridine in me-tllylene chloride
(8 ml) is reactecl witll 115 ml oE brominc in methylene chloride. After 30
minutes, startin~ nlaterial has completely disappearecl; the organic phase is
~ashed ~ith wa-ter, then 5~ aqueous metabisulfite, and then ~ater until neu-
/~
~31~
tral to give, after removal of the solvent and purification by TLC on silica
gel with ethyl ether as eluent, 0~083 g of 16,16-dimethyl-5-bromo-6~H-6(9a)-
oxide-prostanoic acid methyl ester and 0.04 g of 6c~l-diastereoisomer.
The following compounds were p:repared analogously:
13t-16,16-dimethyl-5-bromo-6~H-6(9a)-oxide-lla~15S-dihydroxy-prost-13-enoic
acid;
13t-16,16-dimethyl-5-bromo-6aH-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-9,lla,15S-
trihydroxy~l8,19,20-trinor-17-cyclohexyl-prost-5,13-dienoic acid methyl ester-
11,15-bis-tetrahydropyranyl ether (0~7 g) in 6 ml of tetrahydrofuran. The
mixture is stirred for 12 hours, the precipitate 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 Tl.C gi~es 0.14 g of 13t-5-bromo-6aH-6~9a)-oxide-
lla,15S-dihydroxy-18gl9,20-trinor-17-cyclohexyl-prost-13-enoic acid methyl
ester and 0~11 g of the 5-bromo-6~-6(9a)-oxide.
Using procedures of the examples 95 and 96, the following 6(9a)-
oxides were obtained;
5-bromo~6~1~6~9c~ oxide-lla,155-dihydroxy-18,19~20-trinor-17-cyclohexyl-
prost-13~ynoic acid mothyl ester;
5-bromo-6 ~l-6~9a)-oxide-lla,15S_dihydroxy-prostanoic acid;
~3 ~c~
~3~2
13t-5-bromo-6~H-6~9a)-oxide-lla,15S~dihydToxy-prost-13-enoic acid;
13t-20-methyl-5-bromo-6~H-6(9a)-oxide-lla,15S-dihydroxy-prost-13-enoic acid;
13t-15-methyl-5-bromo-6~H-6(9a)-oxide-lla,15S-dihydroxy-prost-13-enoic acid;
13t-15-methyl-5-bromo-6~H-6(9a)-oxide-lla,15S-dihydroxy-prost-13-enoic acid;
13t-16S-methyl-5-bro~o-6~H-6C9a)-oxide-lla,15S-dihydroxy-prost-13-enoic acid;
13t-5-bromo-6~H-6~9a)-oxide-lla,15S-dihydroxy-18,19,20~trinor-17-cyclohexyl-
prost-13-enoic acid;
13t-5-bromo-6~H-6(9a)-oxide-lla,15S-dihydroxy-17,18,19,20-tetranor-16-m-tri-
fluoromethyl-phenoxy-prost-13-enoic acid.
Example 97
A solution of 0~1 x 10 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 lithium 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 extract~d
with ethyl ether.
The organic phase is washed with 0.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.
