Note: Descriptions are shown in the official language in which they were submitted.
s~
The pre~ent in~ention ~s concer~ed with nsw cyclopentane
dlerivative~ and with their ma~u~acture and u3eO
The present inventlon provides compounds oi the ge~eral
iormula I
J~ ' .
" ~ (I3
~ B ~ ~
O
~2 ,
in whi¢h
B represents a -oH2-C~2- or a tran~ -o~E- group,
represents a methyl or ethyl group and
0~ repres~nt~ a hydroxyl group, a~ acylo~y group or an
etheriiied hydro~yl group.
~ etherii~ed hydroxyl group~ and acyloxy group~ represented
by ~ there come into consideration group~ kno~n to the e~pert.
Preierred etheriiied hydro~yl group~ are tho~e that can be aplit
oii ea~ily cr under mild conditio~; thero may be mentioned b~
way oi example tetrah~dropyranyl, tetrahydro~uranyl, a-etho~yethyl,
tr~methyl~ tr~-para-~ylyl-æilyl and dimethyl-tertO-butyl-silyl
group~O There ma~ be mentioned a~ a~ylo~y groups those in which
the acyl group~ pre~erably contain up to 15 carbon atoms,
pre~erably ac~tyl, propio~yl, butyryl, ben~oyl and paraphenyl-
ben20yl group~.
~69 ~
The pre~ent inventio~ al~o provides a proces~ ~or ~he
ma~u~acture o~ the compound~ o~ the general ~ormula I,
wh~rein an alde~yde o~ the general ~ormula II
OR2
in which O~ repre~ent~ an acylogy group or an etheri~ied
hydro~yl group, i~ reacted ~7ith a pho~phorane of the general
formula III
- (c6H5~3p=o~ C ~ (III) 9
in which Rl ha~ the meaning given above, or wlth a pho~pho~ate
oi the general iormula IV
O O
( ~ 0)2P--~H2~
in wh~ch ~ ha3 the meani~g given above, and, li de3ired, ln the
re~ulting compound the carbon-to-oarbon tran~ double bond i~
hydrogenated to form a ~ k~ carbon-to-carbon ~ingle bond a~d/or
the acylo~y group or th~ etheriiied hydroxyl group iB ~o~verted
into a ~ree hydro~yl groupO
~ he etep or steps in the pro¢ess oi the present inventio~
may be carried out ln a known mannerO
- 3 ~
- .. . .
, ... . . .
~ ~69 ~ ~
The reaction with the pho~phorane may be e~ected iQ a
m~ner known ~E ~e ~n an l~ert solvent9 ~or example be~ene,
toluene, xylene, diet~yl ether, tetrahydro~uran, dioxan, chloro~orm,
di~ethyl ~ulpho~ide, methylene chloride or dimethyl~ormamide, at
a temperature wlthin the range of ~ro~ 0C to 100a, preferably
at 25C. ~he reaction with a phosphonate may b~ carried out i~
th~ presence o~ a cataly~t, ior e~ample butyl llthium or ~odium
hydrid~, in a sol~ent, *or exa~ple dimetho~yeth~ne, diethyl ether,
t~trahydro~uran or dioxa~, at a temperature ~ithin the range o~
~rom ~oa to -70C, pre~erably -20C to 0C0
When B represents a -CE2-oH2- group in the de~ired end
product, the carbon-to-carbon double bond in the product oi the
reaction with the phosphorane or the pho~phonate i~ hydrogenatedO
~he hydrogenation may be carried out according to a method known
~E se~ It 1~ pre~erably carried out ln the presence oi a noble
~etal cataly~t, ior example lO~o palladium on carbon, in an
inert solvent, ior example methanol or ethyl acetate, at room
temperature and under normal preseure.
The llberatlon oi the iunctionally converted hydro2yl
group3 to iorm compound~ oi the general iormula I in which OR2
represe~t~ a hydroxyl group may be carried out according to a
known methodu For example, an ether protective group is split
oii in an aqueou~ ~olutlon o~ an organic acid, ior example
acetic acid or propionlc acid, or in an aqueou~ ~olution o~ an
inorganic acid, ior example hydrochloric a~id or tetrabutyl
ammonium iluoride. In order to improve ~olubility, it 1~
advantageou~ to add an inert, organic ~olvent mi~cible with water.
. ~ , . .
.
~06~35~
S~itable organic sol~ent~ are, ior e~ample, alcohol~, rOr e~am~le
methanol and ethanol, and ether~, *or e~ample dimeth~ ogyethane,
dioxa~ and tetrahydro~uran. Tetrahydro~ura~ ie pre~erably u~edO
The splitting o~ proce~ pre~erably e~ected at a temperature
~ithln the range o~ ~rom 20C to 80Co
The hydroly~is o~ a~ acyl group ls carried out, ~or e~ample,
with a~ alkal~ me~al or alkaline earth metal carbonate or
hydro~ide in an alcohol or an a~ueou~ solution of an alcoholO
alcohola there come into con~id~ration al~phatic alcohol~,
for example methanol, ethanol or butanol, but preierably methanolO
~lk~l~ metal carbonate~ and hydroxides there may be mentioned
potassium and sodium carbonates and hydroxides, but potass~um
carbonate and potassiu~ hydroxide are pre~erredO ~8 alkaline
earth metal carbonate~ and hydroxidea there are ~uitable, ~or
example, calc$um carbonate, calcium hydroxide and barium carbonate.
~he reaction takes place at a temperature within the range o~
~rom -10C to 70C, preierablg at 25Co
The compounds of the general iormula I are out~tanding3.y
~uitable intermediates ior producing prostaglandin derivative~0
; ~ccordi~g to~the prostaglandin syntheses hitherto known~
as de~cribed, ior example, ln German Oi~enlegungsschrift No.
2~47,6~0, the production o~ compounds ha~ing unitary ~tereo-
chemistry at the C-atom 15 requires estraordinar~ly expensive
apparatus and preparati~e separating operations.
~ ccordinglg, there has existed the problem oi developi~g
a proce~s or method ior obtaining in a uimple manner auch ¢ompound~
having unitary ~tereochemiatrg a~ the C-atom 150
- 5
~06'~5~
~ he compound~ oi the general ~ormula I are e~pecially
e~table fo~ achleving thi~ aimO
The pre~e~t inventio~ accordingl~ ~urther provide3 a proce~
ior the manu~acture oi 13,14-dihydro-15-methyl or -ethyl-P~F2a
or a derlvative thereoi, wherein a compound oi the general ior~ula
I g~ven above, in which ~, ~ and O~ have the meanings given
above, i~ reacted ~Jith a compou~d o~ the ge~eral formu~a V
M-C-C-C$2-CE2~ 3 (V)
in ~hioh ~ repreæent~ a metal atom equivalent or a metal-
contain~ng group, and the re~ulting compound o~ the general
io~mula Vl
. i~ ~
~ ~C-C CH ~H ~ (VI) ,
~2 OH
~ which B, ~ and OR2 have the meaning~ given above, i~ converted
into 1~,14-dih~dro-15-methyl or -ethyl-PG~2~ or a derivative
thereoiO
Ths ketone~ oi the general iormula I are easy to prepare by
the proces~ oi the present inve~tion and9 aiter reaction with an
organo-metal compound o~ the general fo~mula V, can be iurther
prooe~sed is a 3imple manner to iorm the kno~n 13,14-dihydro-15-
methyl or -ethyl-PGF2 and derivatives thereo~.
. .
~ 6 -
',, : ', ` ' ' "." ''~ . ., . ' . ' ' :. ' '
:' : :; ' " . ' '' : ~
~36g50~
~ he reaction o~ a compound o~ the general ~ormula I with
orga~o~metal compol-~d o~ the general ~ormula Y i~ oarried out
i.n a manner known ~er ~e in an inert ~olvent or inert ~olvent
mi~ture, ior e~ample diethyl ether, tetrahydro~uran~ dioxan or
dLimetho~yethane, but pre~erably diethyl ether. The reaction i~
~ected at a temperature within the raDge o~ ~rom 100~ to
60C, and preferably -60C to -30Co
The compound o~ the general iormula ~ ~ece~ary ~or ~hi~
reaction i~ prepared by reacti~g the corre~ponding termi~al
acetylene-hydrogen compound (M=H) with a~ orga~o-metal compoundO
A~ orga~o-metal compound~ there come into con~ideratio~ lithium
butyl, lithium methyl, lithium ethyl, lithium propyl, lithium
phenyl, methyl magneeium bromide9 ethyl magne~ium bromide, propyl
magne~ium bromldej~butyl magnesium bromide, but preferably litb.ium
butyl and methyl magne~ium bromideO
~ he s~mbol M oi the general formula V accordingly prs~erably
repre~ent~ an alkali metal atom or an alkali~e earth me~al-
halogen groupO ~ advantageously represents a lithium atom or a
magnesium-bromine group.
~ he ~pimeric al5 alcohol tPG numbering~ of the general
~ormula VI ~ormed b~ the reaction of the compound of bhe general
~ormula I with the compound o~ the general formula V can be split
: up into the two epimers very easily with ~exy good y~eld~ by a
method known ~er se, ~or example by ~iltration through ~ilica
gel or alumi~ium oxideO
.,
..
... . , , , ~,
;
. ~069S~
The compound o~ the general iormula Vl i~ the.~ hydrogenated
according to a method known ~ æe in order to convert the
carbon-to-carbon triple bond into a carbon-to-carbon single bond
and any acyl group i~ de~ired, split o~
According to conventional method~ iree hydroxyl group(~)
~s/are etheri~ied, ior e~ample by *orming a tetrahydropyranyl
ethe~, a~d the lactone i8 redueed to the lactol w~th diisobutyl-
aluminium hydrideO The lactol is then reacted in a Wittig
reaction by a k~own method to iorm the desired pro~taglandin
deriYative and, ii de~ired, any protecting group 1~ spl~t o~.
~ he iollowing ~amples illu~trate the invention:-
~am~le 1
.
(lS,5R,6R,7R)-6-[(~)-3-O~o-l-butenyl]-7-ben~oylo~y-2-oxabicyclo-
C3~,0~octan-3-one
. . .
~ o a mixture oi 1046 grams of a ~odium hydride ~uspen~ion
(50% ~trength) in mineral oil and 175 ml o~ dimetho~yethane was
added dropwise, at 20C under argon, a ~olutio~ Or 5010 grams oi
dimethylacetonyl phoephonate in 30 ml oi dimetho%yethane, 1.30
gram~ oi anhydrou~ lithium chloride were added and the whole wa~
etirred ior 2 hours at 20aO ~o thi~ mi~ture ~ae added dropwise
a ~olution o~ 8.3 gram~ o~ (lS,5R,6R,7R)-6-~ormy1-7-ben~oyloxy-2-
o~abicyclo~3,~,0]octan-3-o~e ~JOAmerOchem.~oc. 96, 5865 (1974)~
in 60 ml oi tetrahydro~ura~ at -10C, and the whole was ~tirred
ior 2 hour~ at -10Co ~iter neutralization with glacial acetic
acid, ~00 ml of water were added, extraction was carried out
three times with 150 ~1 oi a saturated ~olutio~ of ~odium bicar-
bonate each tlme and twice with 100 ml oi water each time~
- ~ ~6~ S 0 ~
d~ing was then ¢a~ried out over magne~ium ~lphate and evaporation
wa8 e~fected i vacuo. ~ter chromatography o~ the residue over
siLlica gel, there were obtained with ether 6.80 grams oi the
compound identiiied in the above title a~ colo~rle~ cry~tals,
melting at 62 - 6~C.
The phosphonate used to prepare the compound identlfied
in the above title wa~ prepared a~ iollow8:
l(a) Dimethylacetonyl phosphonate
~ o a ~olution oi 10906 grams o~ iodoacetone ~n 75 ml o~
benzene were added dropwi~e, at 50 - 55C, 72.1 gram~ of trimethyl
pho~phite and the resulting methyl iodide wa~ continuously
di~tilled oiiO Heating under reilu~ wa~ then ef~ected for 1 hour
and, a~ter di~tillation at 15 torr and 128 - 135C, 55 gram~ o~
dimethylacetonyl pho~phonate were obtained as a colourle~, clear
liquid~
Example 2
13,14-Dihydro-15-methyl-proctagland~ n F2a
(a) (lS,5R,6R,7R,3lR)-6~ )-3-Hydroxy-3-methyl-oct-1-en-4-
yn-l-yl]-7-benzoyloxy-2-oxabicyclo~3,3,0]octan-3-one
~ o a solution of 5.35 gram~ o~ the ketone prepared a~ de~-
cribed in E~ample 1 in 160 rl oi ether and 160 ml oi tetrahydroPuran
were added dropwise, at -70C under argon, 7806 ml oi a lithlum
pentyne ~olution (preparation: to a solution oi 299 gram~ of
pentyne-l ~n 57 ~1 o~ tetra`hydro~uran were added dropwise, at
-70C under argon, 19.7 ml o~ a 2M lithium butyl solution in
hexane and the whole wa~ stirred ~or 10 minute~ at -70C).
g_ .
.
, ~: , , . , .,. ~ . . ,
~' ~ . ''. ' ' . ':
~N~3 ~ ~t~
The whol~ was stlrred ~or one hour a~ -70~, 50 ml of a
saturated ammonium chloride ~olution were added, the mixture ~a~
al.lowed to warm up to room temperature, e~traction wa~ carried
out three times wlth 150 ml o~ ether each time, the organic phase
wa~ ~haken twice with 70 ml of water each time, drying was
e~ected over magnesium sulphate a~d evaporat~o~ was carried out
in vacuo. A~ter chromatography over ~ilica gel (deactivated wi~h
3~ o~ water) there ~ere obtained with pentane/ether (1:1) 1.82
grams o~ the compou~d identi~ied in the above heading (15a-hydroxy)
as a colourless oil and, as the more polar component, 1062 grams
o~ the 15~-or~entated (according to the PG numbering) compound
(lS,5R,6R,7R,3'S)-6-~tE~ hydroxy-3-methyl-oct-1-en-4-yn-1-yl~-
7-benzoyloxy-2-oxabicyclo[3,3,0]octan-3-one as a colourless oilO
DC (ether) 15R : R~-ralue 0.28
15S s R~-value 0022
IR o~ the 15R-compound meaæured in chloro~orm solution:
3600, 2960, ~9~5, 2875, 2240, 1770, 1715, 1602, 1585, 1450, 1~70,
973/cmO
(b) (lS,5R,6R,7R,~S)-6-(3-Hydroxy-~-methyl-l-octyl)-7-benzoyloxy-
2-o~abicyclo~3~,0]octan-~-one
. , . . _ . . _, . , . . , ~
~ solution o~ 1050 gram~ o~ the compound identified in the
heading o~ Example 2(a) and prepared as de~cribed in E~ample 2(a)
wa~
ln 50 ml of ethyl acetate/shaken, with the addition o~ 60 mg of
palladium (lO~o ~trength on carbon), ~or one hour under an
atmosphere o~ hydrogen at room tempera~ure~ ~fter iiltering and
evaporating the ~olution the residue wa~ chromatographed over
.,'~ , .
- 10 -
, . ,. : ;.. . ,; ;
~C~3 5~ ~
si.l~ca gelO With ~ther/hexane (8+2) 1~3 grams oi the compou~d
id.enti~ied ~n the abo~e heading were obtained a~ a colourle~3 oil.
DC' (ether) Rf ~alue 0030
~he ~MR ~pectrum ~howed no ole~inic proton~.
(c) (1~,5R,6R,7R,3~$)-6-(3-Eydroxy-3-methyl-1-octyl) 7-hgdroxy-
2-oxabicyclo~3,3,0]octan-3-one
To a solution o~ 390 mg o~ the compou~d prepared as de~crlbed
in Example 2(b) ln 20 ml o* methanol were adaea. 140 mg o~ anhgdrons
pota~ium carbonateg a~d ~he whole was stlrred ~or 2 hours at room
temperature under argonO 20 ml o~ OoIN hydrochloric acid were
added, and the whole was diluted with 80 ml o~ a saturated ~olution
o~ sodium chloride, extracted three time~ with 80 ml o~ ethyl
acetate each time, shaken twice with 50 ml of a ~aturated
~olution oi sodium chloride each time, dried over magne~lum
sulphate and evaporated in vacuoO The residue waa ~iltered with
ether/ethyl acetate (7t3) o~er silica gel, and 260 mg of the
compound identi~ied in the above head~ng were obtained as a
colourleq~ oilO
W (ether/dioxan 9~1) R~ value 0.25
IR : 3600, 3300, 2995 9 1770/cmO
- (d) (1$,5R,6R~7R,~S)-6-~3-Methyl-3-(tetrahydropyran-~-ylo~y)~
1-o ~1]-7-(tetrahydropyran-2~102y)-2-oxabicyclo[3,3,0]oct~n~
3-one
~ mixture o~ 300 mg o~ the compou~d prepared a~ de~cr~bed in
Example 2tc), 105 ml o~ dihydropyran, 3 mg o~ para-toluene sulphonic
acid and 15 ml o~ methylene chloride ~Ja~ stirred ~or 20 minutes at
, ~
.
,; ... ...
s~ .
0C~C, diluted with 80 ml o~ methylene chloride, ~haken in ~ucce~ion
wi.th a ~odium bicarbonate solution and a saturated ~olution of
~odium chloride, dried over magne~lum sulphate and eYaporated
to dryne~s in vacuo. The residue was iiltered with ether over
~ilica gel and 390 mg o~ the compound identi~ied in the abo~e
~eading were obtained as a colourless oilO
DC (ether) Ri value 0.5~
IR: 2995~ 2960~ 2930~ 1770~ 1120/cmO
(e) (2RS93aR,4R,5R,6aS~3t~)-4-[3-Methyl;3-(tetrahydropyran-2~
ylo~y)-l-octyl]-5-(tetrahydropyran-2-ylo2y)-perhydrocyclo-
pentatb~uran-2-ol
~ o a solution, cooled to -60C, oi 360 mg o~ the compound
obtained as de~cribed in Example Z(d) in 20 ml o~ toluene were
added dropwl~e, under argon, 3 ml o~ a solutlon oi 20~o ~trength
o~ diisobutyl aluminium hydrlde in toluene, and the whole wa~
stlrred ~or 30 minutes at -60C, the excsss oi rea~ent uas
destroyed by the dropwi~e addition o~ isopropyl ~lcohol, 1051
ml o~ water were added9 the whole wa~ allowed to warm up to room
temperature, stirred ~or a ~urther 30 mi~utes, and diluted with
50 ml o~ methylene chloride, and the resulting precipitate was
$iltered off. A~ter evaporation, 340 mg Qi the compound identifled
in the above heading ~ere obtained a~ a colourle~s oilO
DC (ether) Ri value 0~32
IR: 3600, 3400 (wide), 2985, 2935, 2855/cmO
(~) 13,14-Dihydro-15-methyl-pro~taglandin ~2a-11,15-bis-
~tetrahydropyrany13-ether
~ o a ~olution of lo 75 gram~ o~ 4-carbo~ybutyltriphenyl
phoæphonium bromide in 8 ml o~ dimethyl ~ulpho~ide (DMS0) were
added dropwise at 20~ 709 ml o~ a ~olution o~ methanesulphinyl-
Llethyl sodium in DMS0 (preparation: 378 m~ of a ~uspen~ion of
50% strength oi æodium hydride were dissolved in 709 ml o~ DMS0
auring the course of one hour at 75C), and the whole ~a~ stirred
ror 20 minute3 at 20C. To this solution were added dropwise
440 mg of the compound prepared as de~cribed in ~xample 2(e),
di~#olved in 6 ml oi DMS0, and the whole wa~ ~tirred ~or 2 hours
at 48Co 50 ml of ice ~ater were added to the mixture and e~trao-
tion waæ e~ected three times with 60 ml o~ ether each timeO
This ether extract was di~cardedO The aqueou~ phase was acidi~ied
with an aqueouæ ~olution o~ lO~o strength of citric acid to a
pH-value of 5 and extracted four tlmes with 70 ml o~ an ether/
pentane mixture~ each tim~o The organic phase wa~ ~hake~ with
50 ml o~ a saturatea ~olution of ~odium chloride, dried over
magne3ium ~ulphate and evapora~ed in vacuo. The re~idue waæ
chromatographed with ether over silioa gel and ~20 mg of the
compound identified in the above headirg were obtalned a~ a
colourle~æ oilO
Da tchloro~orm/tetrahydro~uran/acetic acid 10/2/1) Ri value 0.51
IR: (chloro~orm): 3600, 3300 (wide), 2990, 2940, 1710 cm.
(g) 13,14-Di~ydro-15-methyl-pro~taglandin F2
100 mg o~ the bi3-(tetrahydropyranyl)-ether obtained a~
described in ~ample 2(i) were ~tirred with 5 ml o~ a ~ixture oi
glacial acetic acid/water/tetrahydro~uran (65/~5/10) ~or 4 hour3 I,
at 40a, and evaporated to dryness in ~3~ and the re~idue was
- 13 -
~ , . . ." ,
~(~69S04
iiltered with methyle~e chloride/i~opropanol (8~2) over silica
g~l. 50 sng o~ 13,14-dihydro-15~ethyl-prosta1andi~ F2a were
o~tained a~ a colourle~ oilO
W (benzene/dio2an/glaclal acetic acid 20/20/1) R~ ~alue 0028
IX: 3600, 3300 (wide), 3000, 2940, 1705 (wide)/cm.
.
:
J
~'
';~
;;1
-- 14 ~
. . .
