Note: Descriptions are shown in the official language in which they were submitted.
lZ~85Z5
NOVEL CARBACYCLI~S, PROCESS FO~ TE~EIR MANUFACTURE
AND THEIR USE AS MEDICAMENTS
The invention relates to carbacyclin derivatives,
a process for their manufacture and their use as
medicaments.
German Offenlegungsschriften DE-OS 28 45 770,
29 00 352, 29 02 442, 29 04 655, 29 09 088, 30 48 906
and 29 12 409 describe (5E)- and~5Z)-5a-carbaprosta-
glandin-I2 analogues. The nomenclature of the compounds
according to the invention is based on a proposal
~",t~ v
by Morton and Brokow (J. Org. Chem., 44, 2000 [1979]).
The synthesis of these compounds always produces
two double bond isomers which are characterised
by the affix (5E) or (5Z). The two isomers of this
prototype are illustrated by the following structural
formulae:
~ C02H C02H
¢~ ~
HO OH HO OH
(5E)-6a-carbaprostaglan- (5Z)-6a-carbaprostaglan-
din-I2 din-I2
lZ4~35,,'~
It is known from the very comprehensive prior art
on prostacyclins and their analogues that this class
of substance is suitable by virtue of its biological
and pharmacological properties for the treatment
of mammals, including human beings. Their use as
medicaments often encounters difficulties, however,
since they have too short a duration of action for
therapeutic purposes. All alterations of the structure
have the aim of increasing the duration of action
and the selectivity of action.
We have now found that 3-oxa-carbacyclins that
are homologous with respect to the upper chain can
produce a longer duration of action, greater selectiv-
ity and an improved activity.
The present invention provides carbacyclin
derivatives of the general formula
Il
(CH2)n C R
o
fH2
CX
A-W-D-E-R4
~5
12485~5
in which ~1 represents either a radical of the general for-
mula OR2 in which R2 represents a hydrogen a-tom or a Cl-C4
alkyl radical or a radical of the formula -CH2-C-
or a radical of the general formula NIIR3 in which R3 is
hydrogen or 2,3-dihydroxypropyl, X represents a hydrogen
atom or a fluorine atom, A represents a trans-ClI=CH- or
-C--C- group, W reprçsents a hydroxymethylene group, where
the OII group may be in the ~- or ~-configuration, D
represeIlts the group -~-C~I2- or a straight-chain alklylene
~C~2
group with 1 to S carbon atoms or a branched chain alkylene
group with 2 to 5 carbon atoms, E represerlts a -C-C group or
15 ~ ~ a ~ CII~CII3~ g~oup, R4 represents an alkyl radical with 1
to 7 carbon atoms and, when R2 is a hydrogen a-tom, salts
with physiologically acceptable bases.
The present invention also provides salts of
compounds of the general formula I, especially physiologi-
cally tolerable salts thereof. When R2 represents a hydro-
gen atom, for exarnple, salt formation with a base is
possible.
The compounds according to the invention have a
hypotensive and bronchodilative action. They are also suit-
able for vasodilatation and for inhibiting thrombocyte
aggregation and gastric acid secretion.
~ ~ ~ 3 -
:12~85ZS
It will be understood that the structural formulae
and written nomeclature of the compounds described and
claimed herein include, unless otherwise stated, the indi-
vidual isomers and the mixtures of the isomers. Thus, for
example, the compounds of the general formula I are both
(5E)- and (5Z)-isomers.
Suitable alkyl radicals represented by R2 are, for
example, straight- and branched-chain alkyl radicals having
from l to 4 carbon atoms, such as, for example, methyl,
ethyl, propyl, isopropyl, bu~tyl, isobutyl and tert.-bu-tyl.
A methyl group should especially be mentioned.
- 4 -
1,.~' \
,
~Z41~5Z5
R4 may be straight-chaln or branched alkyl
radicals having 1 to 7 carbon atoms. Examples are methyl,
ethyl, propyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl
and heptyl. Alkyl radicals having 1 to 4 carb~n atoms are
especially preferred.
D may represellt a straight-chain alkylene radical
(i.e. saturated) having from 1 to 5 carbon atoms, or a
branched-chain alkylene. There may be mentioned, for
10example: metnylene, ethylene, 1,2-propylene, ethylethylene,
trirnethylene, tetramethylene, pentamethylene, l-methyl-
tetramethylene, l-methyltrimethylene and l,l-trimethylene-
ethylene.
15Thus, DER4 may represent, for example,
lCl33 ICH3
-CH-CH2-C----C-CH3, -CH-CH2-C--C-CH2-CH3 ,
CH CH
1 3 1 3
-C-CH2-C--C-CH3, -Cl-CH2-C----C-CH2-CH3, , I
CH3 C~3
ICH3 ~CH3
-CH-CH2-CH=C ~ --C~ CH C~ -CH or
CH3 CH2 /CH2
CH
--~C~ CH2-C--C-CH2CH3
- 5 -
12'~352~
For formation of a salt of a compound of the
general formula I which contains a COOII group (e.g. when R2
represents a hydrogen atom), any inorganic or organic base
may be used, for example a base known to the person skilled
in the art for the
` 'B - 6 -
12~85ZS
~3 -,,;~
formation of physiologically tolerable salts. There
may be mentioned, for example: alkali metal hydroxides,
e.g. sodium or potassium hydroxide; alkaline earth
metal hydroxides, e.g. calcium hydroxide; ammonia;
and amines, e.g. ethanolamine, diethanolamine,
triethanolamine, N-methylglucamine, morpholine or
tris-(hydroxymethyl)-methylamine.
For salt formation with other salt forming
groups in the compound of the general formula I,
an appropriate reagent known to the expert may be
used.
~ he invention also provides a process for the
preparation of a carbacyclin derivative of the general
formula I or a salt thereof, which comprises etherify-
lS ing a compound of the general formula
CH2H
I
- O~ II
A-W-D-E-R4
R5
in which X, R4, R5, A, W, D and E have the meanings
given above, in the presence of a base, optionally
after protecting one or more free hydroxy groups
present, with a haloketal of the general formula
124~5Z~
/R8
Hal-~CH2)3C~ \
ORg
in which Hal represents a chlorine, bromine or iodine atom, each
of R8 and Rg represents an alkyl group havlng from l to 10 carbon
atoms or R8 and Rg together represent a ring-forming group having
from 2 to 10 carbon atoms, and splitting the ketal with acid,
and, if desired, one or more of the following reactions is then
carried out, where appropriate, in any desired sequence, isomers
are separated, one or more protected hydroxy groups is liberated,
one or more free hydroxy groups is esterified or etherified, the
aldehyde group is oxidized., the resulting free carboxy group is
esterified, an esterfied carboxy group is hydrolysed, a carboxy
group is converted into an amide or is converted into a salt.
The reaction of the compound of the general formula II
with a haloketal of the general formula III may be carried out in
a manner known ~E se, suitably, for example, at a temperature in
the range
. 30
;~ 35
- 8 -
X
:`
~ ,
:
: -:
'~
8525
~s ~
of from 0C to 100C, preferably from 10C to 80C,
in an aprotic solvent or mixture of solvents, for
example dimethyl sulphoxide, dimethylformamide or
tetrahydrofuran. Suitable bases are, for example,
those known to the person skilled in the art for
etherification reactions, for example sodium hydride,
potassium tert.-butoxide and butyllithium.
Splitting of the ketal to form a compound of
the general formula I after the etherification reaction
may be carried out according to known methods.
For example, the splitting of the ketal may be carried
out in an aqueous solution of an organic acid, such
as, for example, acetic acid or propionic acid,
or in an aqueous solution of an inorganic acid,
such as, for example, hydrochloric acid. To improve
solubility, advantageously a water-miscible inert
organic solvent is added. Suitable organic solvents
are, for example, alcohols, such as methanol and
ethanol, and ethers, such as dimethoxyethane, dioxane
and tetrahydrofuran. Preferably tetrahydrofuran
is used. The splitting of the ketal is preferably
carried out at a temperature in the range of from
20C to 80C.
The oxidation of the aldehyde group may be
carried out according to methods known tc the person
skilled in the art. Suitable oxidising agents are,
lZ'~85ZS
for example, pyridinium dichromate (Tetrahedron
Letters, 1979, 399), Jones reagent (J. Chem. Soc.
1953, 2555) and platinum/oxygen (Adv. in Carbohydrate
Chem. 17, 169 (1962)).
Oxidation with pyridinium dichromate may be
carried out for example at a temperature in the
range of from 0C to 100C, preferably from 20C
to 40C, in a solvent that is inert with respect
to the oxidising agent, for example dimethyl-
formamide.
Oxidation with Jones reagent may be carried
out for example at a temperature in the range of
from -40C to +40C, preferably from 0C to 30C,
using acetone as solvent.
Oxidation with platinum/oxygen may be carried
out for example at a temperature in the range of
from 0C to 60C, preferably from 20C to 40C,
in a solvent that is inert with respect to the
oxidising agent, such as, for example, ethyl
acetate.
~Z~5~5
~j~.,, //
7 ~ ,,~
Hydrolysis of a carbacyclin ester may be carried
out according to methods kn-own to the person skilled
in the art, such as, for example, using a basic
catalyst.
Introduction of an ester group -OR2 representing
Rl, in which R2 represents an unsubstituted or substitu-
ted alkyl radical (generally having from l to 10
carbon atoms in the alkyl moiety), may be carried
out according to methods known to the person skilled
in t~e art. The carboxy compound may be reacted,
for example, with a diazo hydrocarbon in a manner
known E~ se, for example by mixing a solution of
the diazo hydrocarbon in an inert solvent, preferably
in diethyl ether, with the carboxy compound in the
same inert solvent or in a different inert solvent,
such as, for example, methylene chloride. After
the reaction is complete, i.e. usually in from l
to 30 minutes, the solvent may be removed and the
ester purified in customary manner. The diazo-
alkanes are known or may be manufactured accordingto known methods [Org. Reactions, Vol. 8, pages
389-394 (1954)].
.
,
lZ4~5Z5
Introduction of an ester group -OR2 representing
Rl, in which R2 repr-esents the diphenyl radical, may be
carried out according to methods known to the person skilled
in the art. For example, the carboxy compound and the cor-
responding diphenylhydroxy compound may be reacted withdicyclohexyl carbodiimide in the presence of a suitable
base, for exa~ple pyridine or triethylamine, in an inert
solvent. Suitable solvenls are, for example, me-thylene
chloride, ethylene chloride, chloroform, ethyl acetate and
tetrahydrofuran, preferably chloroform. The reaction may be
carried may be carried out, for example, at a temprature in
the range of from -30C to +50C, preferably at +10C.
In-troduction of an ester group -OR2 representing
Rl may also be carried out by reac-ting the carboxylate anion
with an appropriate alkyl halide or haloketone (Hal-CH2-C-Ar
in which Ar represents diphenyl).
A carbacyclin derivative of the general formula I
in which Rl represents a hydroxy group (R2=H) may be con-
verted into a salt by neutralisation using a suitable amount
of the corresponding inorganic base. The solid inorganic
salt may be obtained, for
~ ie - 12 -
1248525
example, by dissolving the corresponding acid in
water that contains the stoichiometric amount of
the base and then evaporating off the water or adding
a water-miscible solvent, for example an alcohol
S or acetone. Preparation of an amine salt may be
carried out in customary manner. For example, the
carbacyclin acid is dissolved in a suitable solvent,
such as ethanol, acetone, diethyl ether or benzene,
and at least the stoichiometric amount of the amine
10 is added to this solution. The salt generally forms
in solid form or may be isolated in customary manner
after evaporation of the solvent.
Functional modification of a free OH group(s)
may be carried out according to methods known to
15 the person skilled in the art.
For the introduction of an ether protecting
group(s), reaction is carried out, for example,
with dihydropyran in methylene chloride or chloroform
using an acid condensation agent, such as, for example,
20 P-toluenesulphonic acid. The dihydropyran is advan-
tageously used in excess, preferably in an amount
that is from 4 to 10 times greater than the theoretical
requirement. At from 0C to 30DC the reaction is
normally complete after from 15 to 30 minutes.
Introduction of an acyl protecting group(s~
may be carried out by reacting a compound of the
1;248SZS
general formula I in a manner known per se witha carboxylic acid derivative, such as, for example,
inter alia, an acid chloride or acid anhydride.
Liberation of a functionally modified OH group(s)
may be carried out according to known methods.
For example, an ether protecting group(s) may
be split off in an aqueous solution of an organic
acid, such as, for example, acetic acid or propionic
acid, or in an aqueous solution of an inorganic
acid, such as, for example, hydrochloric acid.
To improve solubility, advantageously a water-miscibie
inert organic solvent is added Suitable organic
solvents are, for example, alcohols, such as methanol
and ethanol, and ethers, such as dimethoxyethane,
dioxane and tetrahydrofuran. Preferably tetrahydro-
furan is used. Splitting off is preferably carried
out at a temperature in the range of from 20C
to 80C.
A silyl ether protecting group(s) may be split
off, for example, with tetrabutylammonium fluoride.
Suitable solvents are, for example, tetrahydrofuran,
diethyl ether, dioxane and methylene chloride.
Splitting off is perferably carried out at a tempera-
; ture in the range of from 0C to 80~C.
2~ Hydrolysis of an acyl groups(s) may be carried
out, for example, with an alkali metal or alkaline
,
~'
124~ 5
s~
earth metal carbonate or hydroxide in an alcoholor the aqueous solution of an alcohol. Suitable
alcohols are, for example, aliphatic alcohols,
such as, for example, methanol, ethanol and butanol,
preferably methanol. Suitable alkali metal carbonates
and hydroxides are, for example, potassium and
sodium compounds, the potassium compounds being preferred.
Suitable alkaline earth metal carbonates and hydroxides
are, for example, calcium carbonate, calcium hydroxide
and barium carbonate. The reaction is generally
carried out at a temperature in the range of from
-10C to 70C, preferably at 25C.
Introduction of an amide group NHR3 representing
Rl may be effected according to methods known to
the person skilled in the art. For example, the
carboxylic acid of the general formula I (R2=H)
may first be converted, in the presence of a tertiary
amine, such as, for example, triethylamine, into
the mixed anhydride using chloroformic acid isobutyl
ester. The reaction of the mixed anhydride with
the alkali metal salt of the corresponding amide
or with ammonia (R3=H) may be carried out in an
inert solvent or mixture of solvents, such as, for
example, tetrahydrofuran, dimethoxyethane, dimethyl-
formamide or hexamethylphosphoric acid triamide,at a temperature in the range of from -30C to +60C,
.
; ~ ~
~ .
: ~
i;Z48S25
preferably at 0C to 30C.
It is also possible to introduce the amide
group NHR3 representing Rl by reacting a l-carboxylic
acid of the general formula I (R2=H), in which
one or more free hydroxy groups are, if desired,
intermediately protected, with a compound of the
general formula
O = C = N - R3 IV
in which R3 has the meaning given above.
The reaction of the compound of the general
formula I (Rl=OH~ with an isocyanate of the general
formula IV may be carried out optionally with the
addition of a tertiary amine, such as, for example,
triethylamine or pyridine. The reaction may be
lS carried out without a solvent or in an inert solvent,
preferably acetonitrile, tetrahydrofuran, acetone,
dimethylacetamide, methylene chloride, diethyl
ether or toluene, at a temperature in the range
of from -80C to 100C, preferably at from 0C
to 30C.
If the starting material contains one or more
OH groups in the prostane radical, then these OH
groups are also reacted. If the ultimate aim is
to produce an end product that contains one or
more free hydroxy groups in the prostane radical,
~; .
12~8525
it is advantageous to use a starting material in
which these hydroxy groupts) are intermediately
protected by an ether or acyl radical that can
preferably be readily split off.
Compounds of the general formula II which serve
as starting materials may be manufactured, for
example, by, in a manner known ~ se, reacting
an aldehyde of the formula
V,
~ CHO
(DE-OS 28 45 770) in the presence of a deprotonating
agent, such as, for example, sodium hydride or
potassium tert.-butoxide, with a phosphonate of
the general formula
O O
CH30~
/ P - CH2 - C - D - E - R4 VI
CH30
in which D, E and R4 have the meanings given above,
to form a ketone of the general formula
.
.
, .
lZ'~35'~5
o o
X VII
O~CH=CZ-C-D-E-R4
O
(Z=H), or alternatively in the presenlce of a brominat-
ing agent, such as, for example, N-bromosuccinimide,
to form a ketone of the general formula VII (Z-Br).
Reduction of the keto group with zinc borohydride
or sodium borohydride or reaction with alkylmagnesium
bromide or alkyllithium and subsequent separation
of the epimers yields compounds of the general
formula
O O
X VIIl
~J~CH=CZ_W_D_E_R4
OCO ~3
Hydrolysis of the ester group, for example
with potassium carbonate in methanol, and optional
.
~,; ' ` . , .
~ -
: , ,
~24~525
hydrogenation of the double bond or optional etheri-
fication with dihydropyran and subsequent removal
of hydrogen bromide using, for example, potassium
tert.-butoxide in dimethyl sulphoxide, ketal-splitting
S with agueous acetic acid and also optional functional
modification of the free hydroxy groups, for example
by etherification with dihydropyran, yields the
ketone of the general formula
A~W-D-E-R4 IX
R5
An olefination reaction with phosphonoacetic
acid triethyl ester or phosphonoacetic acid trimethyl
ester or with phosphonofluoroacetic acid triethyl
ester or phosphonofluoroacetic acid trimethyl ester
and subsequent reduction with lithium aluminium
hydride yields compounds of the general formula II
which are isomeric with respect to the double bond
and which may, if desired, be separated.
A phosphonate of the general formula VI may
be manufactured in a manner known per se by reacting
the anion of methylphosphonic acid dimethyl ester
with an ester of the general formula
~Z4~5~5
s~ ~
~ C - D - E - R X
Rl oO
in which D, E and R4 have the meanings given above
and Rlo represents an alkyl radical having from
1 to 5 carbon atoms. This may if desired be obtained
from the corresponding malonic acid ester by alk,yla-
tion with a halide of the general formula
Hal - E - R4 XI
(in,which Hal represents chlorine or bromine) and
subsequent decarbalkoxylation.The ester of the general
, 10 formula X may if desired be obtained also from
the carboxylic acid of the general formula
HO - C - D XII
in which D has the meaning given above, by alkylation
with a halide of the general formula XI and subsequent
esterification.
; Compounds of the general formula III which
serve as starting materials can be manufactured,
for example, in a manner known per se, hy reducing
an ~-halocarboxylic acid ester of the general formula
"
, .Al -
~.;
. .
12'~1~525
Hal-(CH2)3 -COORll XIII
in which Hal and a have the meanings given above and Rll
represents an alkyl group having from l to 5 carbon atoms, with
diisobutyl aluminium hydride to form the corresponding aldehyde
and subsequently, in a known manner, ketalising it with an
alcohol.
The compounds of this invention have a hypotensive and
bronchodilative action. They are also suitable for the inhibi-
tlon of thrombocyte aggregation. Consequently, the carbacyclin
derivatives of the formula I and their physiologically tolerable
salts are useful pharmaceutical active substances.
, .
.
- 21 -
':
~z4~ilS~S
Furthermore, whilst having a similar spectrum of
orostaq I c~?C~ S
action compared with corresponding ~ octac~clin~,
they exhibit higher specificity and, above all,
substantially longer activity. In comparison with
PGI2 they are distinguished by greater stability.
The high tissue specificity of the prostaglandins
of the invention is apparent in studies on smooth-
muscle organs, such as, for example, the ileum of
guinea pigs or the isolated trachea of rabbits,
where a substantially lower stimulation is to be
observed than in the case of administering natural
prostaglandins of the E, A or F type.
The carbacyclin analogues of the invention
possess proper'iés typical of prostacyclins, such
as, for example, reduction of the peripheral arterial
and coronary vascular resistance, inhibition of
thrombocyte aggregation and breaking up of platelet
thrombi, myocardial cytoprotection and, therewith,
lowering of the systemic blood pressure without
simultaneously reducing cardiac output and coronary
blood flow; treatment of stroke, prophylaxis and
therapy of coronary heart diseases, coronary thrombo-
sis, cardiac infarct, peripheral artery diseases,
arteriosclerosis and thrombosis, prophylaxis and
therapy of ischaemic attacks of the central nervous
system, therapy of shock, inhibition of bronchocon-
striction, inhibition of gastric acid secretion and
: `
- ~24~5~S
cytoprotection of the gastric and intestinal mucosa,
cycoprotection in the liver and pancreas; anti-allergic
properties, reduction of pulmonary vascular resistance
and of pulmonary blood pressure, stimulation of
the blood flow through the kidneys, use instead
of heparin or as adjuvant in the dialysis of haemo-
filtration, preservation of blood plasma supplies,
especially blood platelet supplies, inhibition of
labour pains, treatment of toxaemia in pregnancy
and increase in cerebral blood flow. In addition,
the carbacyclin derivatives of the invention have
anti-proliferative and anti-diarrhoeal properties.
They may be used also in combination for example
with ~-blockers or diuretics.
The dosage of the compounds is advantageously
from 1 to 1500 ~g/kg/day when administered to human
patients. Preferably the amount of active ingredient
per unit dose is from 0.01 to 100 mg.
In the case of intravenous injection to conscious
hypertonic rats in doses of 5, 20 and 100 ~g/kg
body weight, the compounds according to the invention
~- have a greater hypotensive and longer-lasting action
than do PGE2 and PGA2, without causing diarrhoea,
as does PGE2, or cardiac arrhythmia, as does PGA2.
In the case of intravenous injection to narcotised
rabbits, the compounds according to the invention
,
`: :
.
.
12'~5~S
cause a greater and considerably longer-lasting
decrease in blood pressure compared with PGE2 and
PGA2, without other smooth-muscle organs or organ
functions being influenced.
For parenteral administration, sterile, injectable
aqueous or oily solutions may be used. For oral
administration, tablets, dragees or capsules, for
example, are suitable.
The active substances according to the invention
may serve, in combination with the adjuncts known
and customary in galenical pharmacy, for example,
for the manufacture of hypotensive agents.
Accordingly, the present invention provides
a pharmaceutical preparation which comprises a compound
of the general formula I or a physiologically tolerable
salt thereof, in admixture or conjunction with a
pharmaceutically suitable carrier. Suitably the
preparation is in dosage unit form.
The following Examples illustrate the invention.
The 15-hydroxy group of the compounds in the Examples
corresponds in configuration to the 15-hydroxy group
;~ in 6a-carbaprostaglandin-I2.
~24852S
l~xample
(5E)-~16RS)-2-decarboxy-la, lb-dihomo-2-formyl-16-methyl-3-
oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2
77 mg of 55 % sodium hydride ~u~pension in mineral
oil is added at 0C to a ~olution of 700 mg of 2-
~(1_,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(E)-
(3S,4RS~-~-methyl-3-(tetrahydropyran-2-yloxy)-oct-1-
en-6-ynyl~-bicyclo[3.3.0~octan-3-ylidene~-ethan-1-ol
in 15 ml of tetrahydrofuran and the whole is stirred
for 30 minutes at 24 C under argon. A solution of
1.15 g of 2-(3-bromopropyl~-1,3-dioxolane in 7 ml of
tetrahydrofuran is subsequently added dropwi~e thereto
and the whole is refluxed for 21 hours under argon.
The solution is dil~ted with ether, washed until neutral
with water, dried over magnesium sulphate and concen-
trated by evaporation in vacuo, Chromatography of the
residue over silica gel with hexane/ether (7+3) yields
480 mg of the oxa compound which is stirred with ~0 ml
of a mixture of acetic acid/water/tetrahydrofuran
(65~35+10) for 16 hours at 24C. The whole is subse-
quently concentrated by evaporation in vacuo and the
residue is chromatographed over silica gel. Using
ethyl acetate~hexanc (4+1), 270 mg of the title com-
pound in the form of a colourless oil are obtained.
IR (CHC13): 3600, 3420 (broad), 2970, 2862, 2730,
1725, 1603, 970/cm.
2~5~5
The 2-(3-bromopropyl~-1,3-dioxolane used for the
above etherification reaction is manufactured as follows:
50 ml of a 1.2 molar solution of diisobutyl alu-
minium hydride in toluene iq slowly added dropwise at
-70C to a solution of 9.6 g of bromobutyric acid ethyl
ester in 595 ml of toluene, the whole is stirred for
15 minutes at -70C and then 10 ml of isopropyl alcohol
and 25 ml of water are added dropwise thereto. The
whole is stirred for 2 hours at room temperature and
filtered, the filtrate is dried using magnesium sulphate
and concentrated in vacuo at 25C. The residue i~
dissol~ed in 500 ml of toluene, 10 ml of ethylene
glycol and 100 mg of ~-toluenesulphonic acid are added
and the whole is refluxed for 6 hours using a water
~eparator. The mixture is subseguently diluted with
500 ml of ether, shaken once with a 5 % sodium bi-
carbonate solution and three times with water and
.. the organic extract is dried using magnesium sulphate
and concentrated in vacuo at 30 C. Distillation of
the residue at 0.6 torr and 43 - 45C yields 6.8 g
of 2-(3-bromopropyl~-1,3-dioxol~ne in the form of a
colourless liquid.
Ex~mDle 2
(5E)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-
tetradehydro-6a-carbaprostaglandin-I2
_
2 ml of acetic anhydride are added to a solution
t:f- ~Z415 5Z5
.
of 500 mg of the aldehyde manufactured according to
Example 1 in 5 ml of pyridine and the whole is left
to stand for 18 hours at room temperature. The solution
is subsequently concentrated _ vacuo and the resulting
- 5 11,15-diacetate is dissolved in 25 ml of acetone and
2.1 ml of Jones reagent are added dropwise at 0 C.
The whole is stirre~ for 30 minutes at 0C, 2 ml of
isopropyl alcohol are added and the whole is diluted
with ether, shaken three times with water, dried over
10 magnesium sulphate and concentrated bylevaporation
in vacuo. Chromatography of the residue over silica
gel with hexane/ethyl acetate (1+1) yieldc 410 mg of
(5E)-(16RS~-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-
tetradehydro-6a-carbaprostaglandin-I2 11,15-diacetate
15 in the form of a colourless oil.
IR: 3650, 3400 (broad), 2960, 1730, 1600, 12~5, 968/cm.
To split off the protecting groups, 410 mg of
the 11,15-diacetate in 20 ml of methanol are stirred
with 520 mg of potassium carbonate for 16 hours at
20 24C. The whole is subseguently concentrated in vacuo,
acidified to pH 4 with 10 % citric acid solution,
extracted three times with methylene chloride, washed
twice with water, dried over magnesium sulphate and
concentrated by evaporation in vacuo. -The residue
25 is chromatsgraphed over silica gel with ethyl acetate/-
acetic acid (99.5 + 0.5). 305 mg of the title compound
are obtained in the form of a colourless oil.
IR: 3590, 3420 (broad), 2960, 2930, 2865, 1720, 1600, 970/cm.
124~S2S
ExamDle 3
(5Z~-(16RS~-2-decarboxy-la,lb-dihomo-2-formyl-16-met~yl-
3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2
Analogously to Example 1, 125 mg of the title
compound are obtained in the form of a colourless oil
from 320 mg of 2- ¦(Z)-(lS,55,6R,7R)-7-~tetrahydropyran-
2-yloxy)-6-~(E)-(3S,4RS)-4-methyl-3-(tetra~ydropyran-2-
yloxy~-oct-l-en-6-ynyl~-bicyclo[3.3.0]octan-3-ylidene~-
ethan-l-ol.
IR: 3610, 3400 ~broad), 2965, 2860, 2730, 1726, 1602,
968/cm.
ExamDle 4
(5Z)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-
tetradehydro-6a-carbaprostaglandin-I2
Analosously to Example 2, 90 mg of (5Z~-(16RS)-
la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-
6a-carbaprostaglandin-I2 11,15-diacetate are obtained
from 125 mg of the aldehyde manufactured according
to Example 3. After splitting off the protecting
groups, 57 mg of the title compound are obtained in
the form of a colourless oil.
IR: 3600, 3410 (broad), 2960, 2866, 1718, 1600, 968/cm.
24~5Z5
Example 5
(5E)-(16RS)-2-decarboxy-la,lb-dihomo-16,20-dimethyl-2-
formyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprosta-
glandin-I2
Analogously to Example 1, 610 mg of the title
compound are obtained in the form of a colourless oil
from 1.35 g of 2-~(E)-(lS,5S,6R,7R)-7-(tetrahydropyran-
2-yloxy)-6-[(E~-(3S,4RS~-4-methyl-3-(tetrahydropyran-2-
yloxy)-non-l-en-6-ynyl~-bicyclo[3.3.0~octan-3-ylidene~-
ethan-l-ol.
IR: 3600, 3410 (broad), 2967, 2862, 2731, 1725, 1601,
970/cm.
The starting material for the above title compound
is manufactured 2S follows:
5a) (lR,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-
~(E)-(3S,4RSj-3-hydroxy-4-methylnon-1-en-6-ynyl]-
bicyclo[3.3.0]octane.
A solution of 9.02 g of 3-methyl-2-oxo-oct-5-ynyl-
phosphonic acid dimethyl ester in 67 ml of dimethoxy-
ethan (DME) is added dropwise at 0C to a suspensionof 1.46 g of sodium hydride (55 % suspension in oil~
in 130 ml of DME and the whole is stirred for 1 hour
at 0 C. A solution of 9.4 g of (lR,5S,6R,7R)-3,3-
ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo[3.3.0]octane
in 130 ml of DME is then added at -20C and the whole
is stirred for 1.5 hours at -20C, poured into 600 ml
Z4~525
of saturated ammonium chloride solution and extracted
three times with ether. The organic extract is washed
until neutral with water, dried o~er magnesium sulphate
and concentrated by evaporation in vacuo. Chromatography
of the residue over silica gel with ether~hexane (1~1)
yields 9.1 g of the a,~-unsaturated ketone in the form
of an oil.
5.2 g of sodium borohydride are added in portions
at -40C to a solution of 9.1 g of the ketone in 300 ml
of methanol and stirring i~ carried out for 1 hour at
-40 C. The whole is subsequently diluted with ether,
washed until neutral with water, dried over magnesium
sulphate and concentrated by evaporation in vacuo.
Column chromatography over silica gel with ether/hexane
15 yields first 3.9 g of the title compound (PG-nomenclature:
15-hydroxy? and then 3.2 g of the isomeric 15~-hydroxy
compound as the more polar component.
IR: 3600, 3400 (broad), 2942, 1711, 1603, 1588, 1276,
968, 947/cm.
5b) (lR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-
[(E)-(3S,4RS)-3-(tetrahydropyran-2-yloxy)-4-
methylnon-l-en-6-ynyl]-bicyclo~3.3.0]octan-3-one
A mixture of 3.6 g of the a-alcohol manufactured
according to Example 5a and 1.4 g of potassium car-
bonate in 120 ml of methanol is stirred for 16 hoursat room temperature ~nder argon. The mixture is
, .
12~ 3525
subsequently concentrated in vacuo, diluted with ether
and washed until neutral with brine. The whole is
dried over magnesium sulphate and concentrated by
evaporation in vacuo. The residue from concentration
S by evaporation is stirred with 75 ml of a mixture
of acetic acid/water/tetrahydr~furan (65~35+10) for
16 hours at room temperature and subsequently concen-
trated by evaporation in vacuo. Filtration of the
residue over silica gel with ethyl acetate/hexane
(7+3) yields 2.2 g of the ketone in the form of an
oil.
A solution of 2.2 g of the ketone, 2.4 ml of
dihydropyran and 23 mg of ~-toluenesulphonic acid in
75 ml of methylene chloride is stirred for 30 minutes
15 at 0C. The solution is subsequently diluted with
ether, shaken with dilute sodium bicarbonate solution,
washed until neutral with water, dried over magnesium
sulphate and concentrated by evaporation in vacuo.
3.4 g of the bis-tetrahydropyranyl ether are obtained
20 whic~ is used without being purified.
IR: 2960, 2865, 1738, 970/cm.
5c) 2-~(E)-(lS,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-
6-E(E)-(3S, 4RS)-4-methyl-3-(tetrahydropyran-2-
yloxy)-non-l-en-6-ynyl]-bicyclo~3.3.0]octan-3-
ylidene~-ethan-l-ol
3.5 g of potassium tert~-butoxide are added to a
solution of 8.1 9 of phosphonoacetic acid triethyl ester
.. --' .
~ 12~25
'~ 3~
in 170 ml of tetrahydrofuran, the whole is stirred for
10 minutes, a solution of 9 g of the ketone manufactured
according to Example 5b in 90 ml of toluene is added
and stirring is carried out for 16 hours at room
5 temperature under argon. The whole is diluted with
1000 ml of ether, shaken until neutral with water, dried
over magnesium sulphate and concentrated by evaporation
in vacuo. The residue is filtered over silica gel
with hexane/ether (3+2). 8.2 g of the unsaturated ester
10 are obtained in the form of a colourless oil.
IR: 2950, 2870, 1700, 1655, 968/cm.
2.2 g of lithium aluminium hydride are added in
portions at 0 C to a stirred solution of 8 g of the
ester manufactured above in 280 ml of ether and the
15 whole is stirred for 30 minutes at 0 C. Excess reagent
is destroyed by the dropwise addition of ethyl acetate,
12 ml of water are added and the whole is stirred
for 2 hours at 22C, filtered and concentrated by
evaporation in vacuo. The residue is chromatographed
20 over silica gel with ether/hexane 13+2). 2.8 9 of
2-~(Z)-(lS,5S,6R,7Rt-7-~tetrahydropyran-2-yloxy)-6-
[(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy~-
non-l-en-6-ynyl]-bicyclo~3.3.0]octan-3-ylidene~-
ethan-l-ol are obtained as the less polar compound
25 and 4.2 g of the title compound in the form of a
colourless oil.
IR: 3600, 3430, 2942, 2863, 1600, 972/cm.
~ `' ' .
.
` 12'~5;Z5
,
ExamDle 6
(5E~-tl6RS~-la,lb-dihomo-16,20-dimethyl-3-oxa-18,18,19,19-
_ _
tetradehydro-6a-carbapro~taglandin-I2
Analogou~ly to Example 2, 305 mg of (5E)-(16RS~-
la,lb-dihomo-16,20-dimethyl-3-oxa-18,18,1g,19-tetrade-
hydro-6a-carbaprostaglandin-I2 11,15-diacetate are
obtained from 380 mg of the aldehyde manufactured accord-
ing to ~xample 5.
After splitting ~ff the protecting groups, 210 mg
of the title compound are obtained in the form of a
colourless oil.
IR: 3600, 3~00 (broad), 2962, 2865, 1720, 1601, 970/cm.
,
Exam~le 7
(5E)-2-decarboxy-la,lb-dihomo-2-formyl-20-methyl-3-oxa-
16~l6-trimethylene-l8~l8~l9~l9-tetradehydro-6a-carba
prostaglandin-I2
Analogously to Examples 1 and 5, 0.4 g of the
title compound is obtained in the form of a colourless
oil from 0.9 g of 2-~(E)-~lS,55,6R,7R)-7-(tetrahydro-
~; 20 pyran-2-yloxy)-6-[tE)-(3R)-3-(tetrahydropyran-2-yloxy~-
; 4,4-trimethylenenon-1-en-6-ynyl~-bicyclo~3.3.0~octan-3-
ylidene~-ethan-l-ol (manufactured according to Example
5a-c from 2-oxa-3,3-trimethylenenon-5-ynphosphonic acid
dimethyl ester).
IR: 3610, 3400 (broad), 2968, 2864, 2730, 1725, 1602,
970jcm.
. ~ .
,
:~
~ ~ .
24~5~S
The starting material for the above title compound
is manufactured as follows:
7a~ 2-~(E~-~15,5S,6R,7R)-7-(tetrahydropyran-2-yloxy-
4,~-trimethylenenon-1-en-6-ynyl]-bicyclo[3.3.0]-
octan-3-ylidene~-ethan-1-ol
_
Analogously to Example 5c, there are obtained from
3 g of (lR,5S,6R,7R~-7-(tetrahydropyrzn-2 yloxy)-6-
[(E~-(3R)-~-(tetrahydropyran-2-yloxy~-4,~-trimethylene-
non-l-en-6-ynyl~-bicyclo[3.3.0~octan-3-one, after
separation of the isomers by chromatography, 470 mg of
2-~(Z)-(lS,5S,6R,7R~-7-(tetrahydropyran-2-yloxy)-4,4-
trimethylenenon-l-en-6-ynyl]-bicyclo~3.3.0~octan-3-
ylidene~-ethan-l-ol as the less polar compound and
690 mg of the title compound in the form of a colourless
oil.
IR: 3600, ~400 (broad), 2945, 2862, 1602, 972/cm.
ExamDle 8
(5E~-la,lb-dihomo 20-methyl-3-oxa-16,16-trimethylene-
18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2
Analogously to Example 2, 295 mg of (5E~-la,lb-
dihomo-20-methyl-3-oxa-16,16-trimethylene-18,18,19,19-
tetradehydro-6a-carbaprostaglandin-I2 11,15-diacetate
are obtained from 400 mg o~ the aldehyde manufactured
according to Example 7.
After splitting off the protecting groups, 220 mg
1ZL~85Z5
3~
of the title compound are obtained in the form of a
colourleq~ oil.
IR: 3610, 3400 (broad), 2960, 2864, 1721, 1602, 970/cm.
Example 9
(5E~-2-decarboxy-la,lb-dihomo-16,16-dimethyl-2-formyl-
3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2
Analogously to Examples 1 and 5, 0.28 g of the
title compound is obtained in the form of a colourle~s
oil from 0.5 g of 2-~(E)-(lS,5S,6R,7R)-7-(tetrahydro-
pyran-2-yloxy)-6-~(E)-(3R)-4,4-dimethyl-3-(tetrahydro-
pyran-2-yloxy)-oct-1-en-6-ynyl]-bicyclo[3.3.0]octan-3-
ylidene ~ ethan-l-ol.
IR: 3600, 3400 (broad), 2965, 2732, 1724, 1600, 970/cm.
ExamPle 10
(5E)-la,lb-dihomo-16,16-dimethyl-3-oxa-18,18,19,19-
tetradehydro-6a-carbaprostaglandin-I2
Analogously to Exam~le 2, 180 mg of (5E)-la,lb-
dihomo-16,16-dimethyl-3-oxa-18,18,19,19-tetradehydro-
6a-carbaprostaglandin-I2 11,15-diacetate are obtained
from 0.27 g of the aldehyde manufactured according to
Example 9.
After splitting off the protecting groups, 120 mg
of the title compound are obtained in the form of a
colourless oil.
IR: 3600, 3400 (broad), 2962, 2865, 1720, 1600, 971/cm.
1248~S
3~
ExamDl e 1 1
(5E)-2-decarboxy-la,lb-dihomo-2-formyl-3-oxa-16,16,20-
trimethyl-18,18,19,19-tetradehydro-6a-carbaprosta-
glandin-I2
~nalogously to Examples 1 and 5, 0.6 g of the
title compound is obtained in the form of a colourless
oil from 1.1 g of 2-~(E)-~lS,5S,6_,7R)-7-(tetrahydro-
pyran-2-yloxy)-6-[(E)-(3R)-4,4-dimethyl-3-(tetrahydro-
pyran-2-yloxy)-non-1-en-6-ynyl]-bicycl,ol3.3.0]octan-3-
I0 ylidene}-ethan-l-ol.
IR: 3610, 3420 (broad), 2964, 2730, 1725, 1602, 972/cm.
Example 12
(5E)-la,lb-dihomo-3-oxa-16,16,20-trimethyl-18,18,19,19-
tetradehydro-6a-carbaprostaglandin-I2
Analogously to Example 2, 0.3 g of (5E)-la,lb-
dihomo-3-oxa-16,16,20-trimethyl-18,18,19,19-tetradehydro-
6a-carbaprostaglandin-I2 11,15-diacetate is obtained
from 0.4 g of the aldehyde manufactured according
to Example 11.
After splitting off the pro.ecting groups,
0.22 g of the title compound is obtained in the
form of a colourless oil.
Il`c: 3610 3400 ~broad), 2964, 2864, 1721, 1600, 972/cm.
.
i24~}525
~L~I 3,~
Example 13
(5E)-(16RS)-2-decarboxy-18,19-didehydro-la,lb-dihomo-
16,19-dimethyl-2-formyl-3-oxa-6a-carbaprostaglandin-I2
Analogously to Examples 1 and 5, 0.4 g of the
5 title compound is obtained in the form of a colourless
oil from 0.7 g of 2-~(E)-(lS,5S,6R,7R)-7-(tetrahydropyran-
2-yloxy)-6-[(E)-(3S,4RS)-4,7-dimethyl-3-(tetrahydropyran-
2-yloxy)-oct-1,6-dienyl~-bicyclo[3.3.0]octan-3-ylidene}-
ethan-l-ol. I
IR: 3600, 3400 (broad), 2966, 2732~ 1725, 1601, 972/cm.
Example 14
(5E)-la,lb-dihomo-16,19-dimethyl-18,19-didehydro-3-oxa-
6a-carbaprostaglandin-I2
Analogously to Example 2, 0.14 g of (5E)-la,lb-
15 dihomo-16,19-dimethyl-18,19-didehydro-3-oxa-6a-carba-
prostaglandin-I2 11,15-diacetate is obtained from
0.2 g of the aldehyde manufactured according to Example
13.
After splitting off the protecting sroups, 90 mg
20 of the title compound are obtained in the form of
a colourless oil.
IR: 3600, 3410 (broad), 2960, 2860, 1720, 1601, 972/cm.
lZ~85~5
3~
45 -
ExamPle 15
(SE)-(16RS)-2-decarboxy-13,14-didehydro-la,lb-dihomo-2-
formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-
carbaprostaglandin-I2
.
Analogously to Examples 1 and 5, 0.29 g o~ the title compound
is obtained in the form of a colourless oil from
0.6 g of 2-~E)-(lS,5S,6S,7R)~7-(tetrahydropyran-2-
yloxy)-6-[(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-
octa-1,6-diynyl]-bicyclo[3.3.0]octan-3rylidene}-ethan-
l-ol.
IR: 3610, 3410 (broad), 2966, 2730, 2225, 1725/cm.
The starting material for the above title compound
is manufactured as follows:
.
15a) 2-~(E)-(lS,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-
6-[(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-
octa-1,6-diynyl]-bicyclo-[3.3.0]octan-3-ylidene~-
ethan-l-ol
Ananogously to Example 5c, there are obtained
from 1.8 g of (lR,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-
6-[(3S,4RS)-4-methyl-3-tetrahydropyran-2-yloxy)-octa-
1,6-diynyl]-bicyclo[3.3.0]octan-3-one, after separation
of the isomers by chromatography, 380 mg of 2-~(Z)-
(lS,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S,4RS)-4-
methyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diynyl]-
bicyclo[3.3.0]octan-3-ylidene}-ethan-1-ol as the less
48525
polar compound and 610 mg of the title compound in
the form of an oil.
IR: 3600, 3400 (broad), 2945, 2860, 2225/cm.
Example 16
(5E)-(16RS)-13,14-didehydro-la,lb-dihomo-16-methyl-3-oxa-
18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2
Analogously to Example 2, 0.21 g of (5E)-(16RS)-
13,14-didehydro-la,lb-dihomo-16-methyll-3-oxa-18,18,19,19-
tetrahydro-6a-carbaprostaglandin-I2 11,15-diacetate
is obtained from 0.4 g of ~he aldehyde manufactured
according to example 15.
After splitting off the protecting groups, 150 mg
of the title compound are obtained in the form of
a colourless oil.
IR: 3600, 3410 (broad), 2960, 2864, 2226, 1718/cm.
ExamPle 17
(5E)-(16RS)-2-decarboxy-13,14-didehydro-la,lb-dihomo-
lS,20-dimethyl-2-formyl-3-oxa-18,18,19,19-tetradehydro-
6a-carbaprostaglandin-I2
:~
Analogously to Examples 1 and 5, 0.42 g of the
title compound is obtained in the form of a colourless
oil from 0.8 g of 2-~(E)-(lS,5S,6S,7R)-7-(tetrahydro-
pyran-2-yloxy)-6-[~35,4RS)-4-metbyl-3-(tetrahydropyran-
~`
~ ' .
12~35:~5
2-yloxy)-nona-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidene-
ethan-l-ol.
IR: 3600, 3400 (broad), 2965, 2732, 2227, 1724/cm.
The starting material for the above title compound
is manufactured as follows:
17a) 2-~(E)-(lS,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-
6-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-
nona-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidene~-
ethan-l-ol
i
Analogously to Example 5c, there are obtained
from 2.1 g of (lR,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-
6-[(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-nona-
1,6-diynyl]-bicyclo[3.3.0]octan-3-one, after separation
of the isomers by chromatography, 450 mg of 2-~(Z)-
(lS,5S,6S,7R)-7-(tetrahydropyran-2-yloxy~6-[(3S,4RS)-4-methyl-3-
(tetrahydropyran-2-yloxy)-nona-1,6-diynyl]-bicyclo[3.3.0]-
octan-3-ylidene}-ethan-1-ol as the less polar compound
and 740 mg of the title compound in the form of a
colourless oil.
IR: 3600, 3420 (broad), 2947, 2862, 2223/cm.
Example 18
(5E)-(16RS)-13,14-didehydro-la,lb-dihomo-16,20-dimethyl-
3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2
Analogously to Example 2, 3qO mg of (SE)-(16RS)-
; .
12~5~5
. ,~
.~ ~
13,14-didehydro-la,lb-dihomo-16,20-dimethyl-3-oxa-
18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2
11,15-diacetate are obtained from 620 mg of the aldehyde
manufactured according to Example 17.
After splitting off the protecting groups, 260 mg
of the title compound are obtained in the form of
a colourless oil.
IR: 3610, 3400 (broad), 2962, 2865, 2225, 1720/cm.
Example 19
(5E)-2-decarboxy-13,14-didehydro-la,lb-dihomo-2-formyl-
20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethyl-
ene-6a-carbaprostaglandin-I2
. , .
Analogously to Examples 1 and 5, 0.18 g of the
title compound is obtained in the form of a colourless
oil from 0.41 g of 2-~(E)-(lS,5S,6S,7R)-7-(tetrahydro-
pyran-2-yloxy)-6-[(3S)-(tetrahydropyran-2-yloxy)-4,4-
trimethylenenona-1,6-diynyl]-bicyclo[3.3.0]octan-3-
ylidene}-ethan-l-ol.
IR: 3600, 3400 (broad), 2965, 2732, 2227, 1724/cm.
The starting material for the above title compound
was manufactured as follows:
,
lZ485Z5
,4'9 -
l9a) 2-~(E)-(15,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-
6-1~3S)-3-(tetrahydropyran-2-yloxy)-4,4-trimethyl-
enenona-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidene~-
ethan-l-ol
-
Analogously to Example 5c, there are obtained
from 3.1 g of (lR,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-
6-[~3S)-3-(t~trahydropyran-2-yloxy)-4,4-trimethylene-
nona-1,6-diynyl]-bicyclo[3.3.0~octan-3-one, a~ter
separation of the isomers by chromatography, 890 mg
Of 2-~(Z)-(lS,5S,65,7R)-7-(tetrahydropyran-2-yloxy)-6-
~(3RS)-3-(tetrahydropyran-2-yloxy)-4,4-trimethylenenona-
1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidene~-ethan-1-ol
as the less polar compound and 1.3 g of the title
compound in the form of an oil.
IR: 3610, 3420 (broad), 2945, 2862, 2226/cm.
Example 20
(SE)-13,14-didehydro-la,lb-dihomo-20-methyl-3-oxa-
18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-
prostaglandin-I2
Analogously to Example 2, 0.32 g of (5E)-13,14-
didehydro-la,lb-dihomo-20-methyl-3-oxa-18,18,19,19-tetrade-
hydro-16,16-trim~thylene-6a-carbaprostaglandin-I2
11,15-diacetate is obtained from 0.42 g of the aldehyde
manufactured according to Example 19.
... . .
~Z4~5'~5
o
After splitting off the protecting groups, 210 mg
of the title compound are obtained in the form of
a colourless oil.
IR: 3600, 3400 (broad), 2963, 2865, 2225, 1720/cm.
5 Example 21
(5E)-2-decarboxy-13,14-didehydro-la,lb-dihomo-16,16-
dimethyl-2-formyl-3-oxa-18,18,19,19-tetradehydro-6a-
carbaprostaglandin-I2
Analogously to Examples 1 and 5, 0.47 g of the
10 title compound is obtained in the form of a colourless
oil from 0.9 g of 2-~(E)-(lS,5S,6S,7R)-7-(tetrahydro-
pyran-2-yloxy)-6-[(3S)-4,4-dimethyl-3-(tetrahydropyran-
2-yloxy)-octa-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidene~-
ethan-l-ol.
15 IR: 3600, 3410 (broad), 2966, 2730, 2225, 1725/cm.
The starting material for the above title compound
is manufactured as follows:
21a) 2-~(E)-(lS,5S,65,7R)-7-(tetrahydropyran-2-yloxy)-
6-[(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-
octa-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidene~-
ethan-l-ol
Analogously to Example 5c, there are obtained
~rom 2.5 g of (lR,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-
6-[(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-octa-
. ' .
lZ~85~5
1,6-diynyl]-bicyclo[3.3.0]octan-3-one, after separation
of the isomers by chromatography, 625 mg of 2-~(Z)-
(lS,5S,6S,7R)-7-~tetrahydropyran-2-yloxy)-6-[~35)-4,4-
dimethyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diynyl]-
5 bicyclo[3.3.0]octan-3-ylidene3-ethan-l~ol as the
less polar compound and 1.1 g of the title compound
in the form of an oil.
IR: 3600, 3400 (broad), 2946, 2865, 2225/cm.
Example 22
(5E)-13,14-didehydro-la,lb-dihomo-16,16-dimethyl-3-oxa-
18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2
Analogously to Example 2, 0.21 g of (5E)-13,14-
didehydro-la,lb-dihomo-16,16-dimethyl-3-oxa-18,18,19,19-
tetradehydro-6a-carbaprostaglandin-I2 11,15-diacetate
5 i9 lobtainea from 0.31 g of the aldehyde manufactured
according to Example 21.
After splitting off the protecting groups 0.14 g
of the title compound is obtained in the form of
a colourless oil.
IR: 3600, 3410 (broad), 2964, 2865, 2225, 1720/cm.
:
, ~
~248SZ5
,~
ExamPle 23
(5E)-2-decarboxy-13,14-didehydro-la,lb-dihomo-2-formyl-
3-oxa-18,18,19,19-tetradehydro-16,16-20-trimethyl-6a-
carbaprostaglandin-I2
-
Analogously to Examples 1 and 5, 0.31 g of the
title compound is obtained in the form of a colourless
oil from 0.8 g of 2-~(E)-(lS,5S,6S,7R)-7-(tetrahydro-
pyran-2-yloxy)-6-[(3S)-4,4-dimethyl-3-(tetrahydropyran-
2-yloxy)-nona-1,6-diynyl]-bicyclo[3.3.l0]octan-3-ylidene~-
ethan-l-ol.
IR: 3610, 3420 (broad), 2965, 2730, 2226, 1724/cm.
The starting material for the above title compound
is manufactured as follows:
23a) 2-~(E)-(lS,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-
6-[(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-
nona-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidene}-
ethan-l-ol
Analogously to Example 5c, there are obtained
from 1.3 g of (lR,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-
6-[(3S)-4,4-dimethyl-3-ttetrahydropyran-2-yloxy)-nona-
1,6-diynyl]-bicyclo[3.3.0]octan-3-one, after separation
of the isomers by chromatography, 300 mg of 2-~(Z)-
tlS~5S~6S,7R)-7-(tetrahydropyran-2-yloxy)-6-¦(3S)-4,4-
dimethyl-3-(tetrahydropyran-2-yloxy)-nona-1,6-diynyl]-
25 bicyclo[3.3.0]octan-3-ylidene~-ethan-1-ol as the less
~' , .
' ::
,
~:
lZ~ 5
~.
~ ~3 -
polar compound and 430 mg of the title compound in
the form of an oil.
IR: 3610, 3400 (broad), 2945, 2865, 2225/cm.
Example 24
5 (5E)-13,14-didehydro-la,lb-dihomo-3-oxa-18,18,19,19-
tetradehydro-16,16,20-trimethyl-6a-carbaprostaglandin-I2
Analogously to Example 2, 0.1 g of (5E)-13,14-
didehydro-la,lb-dihomo-3-oxa-18,18,19 r l9-tetradehydro-
16,16,20-trimethyl 6a-carbaprostaglandin-I2 11,15-
10 diacetate is obtained from 0.16 g of the aldehydemanufactured according to Example 23.
After splitting off the protecting groups, 60 mg
of the title compound are obtained in the form of
a colourless oil.
15 IR:~3600, 3400 (broad), 2965, 2864, 2224, 1718/cm.
,
Example 25
(SZ)-(16RS)-2-decarboxy-la,lb-dihomo-5-fluoro-2-formyl-
16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprosta-
glandin-I2
42 mg of 55 % sodium hydride suspension in mineral
oil are added at 0C to a solution of 420 mg of 2-~(Z)-
(lS,5S,6R,7Rj-7-~tetrahydropyran-2-yloxy)-6-[(E)-
(3S,4RS)-4-methyl-3-(tetrahydrop~-an-2-yloxy)-oct-1-en-
~ 1248525
6-ynyl]-bicyclo[3.3.0]octan-3-ylidene~-2-fluoroethan-1-ol
in 8 ml of tetrahydrofuran and stirring is carried
out for 30 minutes at 24C under argon. A solution
of 630 mg of 2-(3-bromopropyl)-1,3-dioxolane in 8 ml
5 of tetrahydrofuran is subsequently added and the
whole is refluxed for 20 hours under argon. The
mixture is diluted with ether, washed until neutral
with water, dried over magnesium sulphate and concentra-
ted by evaporation ln vacuo. Chromatography of the
10 residue over silica gel with hexane/ether (3+2) yields
340 mg of the oxa compound which is stirred with
30 ml of a mixture of acetic acid/water/tetrahydrofuran
(65+35+10) for 16 hours at 24C. The whole is sub-
sequently concentrated by evaporation in vacuo and
15 the residue is chromatographed over silica gel.
~sinq ethyl acetate/hexane (4+1), 280 mg of the title
compound are obtained in the form of a colourless
oil.
IR: 3600, 3420 (broad), 2960, 2930, 2870, 2730, 1730,
1603, 970/cm.
Example 26
(5Z-)-(16RS)-la,lb-dihomo-5-fluoro-16-methyl-3-oxa-
18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2
Analogously to Example 2, 110 mg of (SZ)-(16RS)-
25 la,lb-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-
~æ4sszs
~ 5 -
.,
tetradehydro-6a-carbaprostaglandin-I2 11,15-diacetate
are obtained from 205 mg of the aldehyde manufactured
according to Example 25.
After splitting off the protecting grou~s, 78 mg
5 of the title compound are obtained in the form of
a colourless oil.
Example 27
(5Z)-(16RS)-2-decarboxy-la,lb-dihomo-16,20-dimethyl-5-
fluoro-2-formyl-3-oxa-18,18,19,19-tetradehydro-6a-
10 caxbaprostaglandin-I2
-
Analogously to Example 25, 370 mg of the title
compound are obtained in the form of a colourless
oil from 610 mg of 2-~(E)-(lS,5S,6R,7R)-7-(tetrahydro-
pyran-2-yloxy)-6-[(3S,4RS)-4-methyl-3-(tetrahydropyran-
2-yloxy)-non-1-en-6-ynyl]-bicyclo[3.3.0]octan-3-ylidene~-
2-fluoroethan-1-ol.
IR: 3610, 3400 (broad), 2963, 2930, 2868, 2731, 1630,
1602, 971/cm.
Example 28
2~ (5Z)-116RS)-la,lb-dihomo-16,20-dimethyl-5-fluoro-3-oxa-
18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2
Analogously to Example 2, 125 mg of (5Z)-(16RS)-
la,lb-dihomo-16,20-dimethyl-5-fluoro-3-oxa-18,18,19,19-
:;
'
lZ4~35;~5
tetradehydro-6a-carbaprostaglandin-I2 11,15-diacetate
are obtained from 230 mg of the aldehyde manufactured
according to Example 27.
After splitting off the protecting groups, 85 mg
of the title compound are obtained in the form of
a colourless oil.
IR: 3600, 3410 (broad), 2965, 2930, 2870, 1720, 1602,
970/cm.
Example 29
t5Z)-2-decarboxy-la,lb-dihomo-5-fluoro-2-formyl-20-
methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethylene-
6a-carbaprostaglandin-I2
Analogously to Example 25, 165 mg of the title
compound are obtained in the form of a colourless
oil from 390 mg of 2-~(Z)-(lS,5S,6R,7_)-7-(tetrahydro-
pyran-2-yloxy)-6-[(E)-(3R)-3-(tetrahydropyran-2-yloxy)-
4,4-trimethylenenon-1-en-6-ynyl]-bicyclo[3.3.0]octan-3-
ylidene~-2-fluoroethan-1-ol.
IR: 3600, 3410 (broad), 2965, 2931, 2870, 2730, 1630,
1601, 970/cm.
ExamPle 30
(5Z)-la,lb-dihomo-5-fluoro-20-methyl-3-oxa-18,18,19,19-
tetradehydro-16,16-trimethylene-6a-carbaprostaglandin-I2
_
Analogously to Example 2, 105 mg of (5Z)-la,lb-
i
...
124~5~ 5
dihomo-5-fluoro-20-methyl-3-oxa-18,18,19,19-tetradehydro-
16,16-trimethylene-6a-carbaprostaglandin-I2 11,15-
diacetate are obtained from 190 mg of the aldehyde
manufactured according to Example 29.
After splitting off the protecting groups, 70 mg
of the title compound are obtained in the form of
a colourless oil.
IR: 3600, 3400 (broad), 2965, 2930, 2870, 1718, 1602,
970/cm.
10 Example 31
(5Z)-2-decarboxy-la,lb-dihomo-16,16-dimethyl-5-fluoro-2-
formyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprosta-
glandin-T2
.
Analogously to Example 25, 0.27 9 of the title
15 compound is obtained in the form of a colourless
oil from 0.6 g of 2-~(Z)-(lS,5S,6R,7R)-7-(tetrahydro-
pyran-2-yloxy)-6-[(E)-(3R)-4,4-dimethyl-3-(tetrahydro-
pyran-2-yloxy)-oct-1-en-6-ynyl]-bicyclo[3.3.0]octan-3-
ylidene~-2-fluoroethan-1-ol.
20 IR: 3610, 3420 (broad), 2966, 2930, 2868, 2732, 1730,
1602, 971/cm.
Example 32
(5Z)-la,lb-dihomo-16,16-dimethyl-5-fluoro-3-oxa-
18,18,19,19-tetradehydro-6a-carbaprostaslandin-I2
Analogously ,to Example 2, 120 mg of (5Z)-la,lb-
'' '
12~85:~5
,,,~ ~ .
dihomo-16,16-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetra-
dehydro-6a-carbaprostaglandin-I2 11,15-diacetate
are obtained from 22Q mg of the aldehyde manufactured
according to Example 31.
After splitting off the protecting groups, 92 mg
of the title compound are obtained in the form of
a colourless oil.
IR: 3600, 3410 (broad), 2964, 2931, 2870, 1720, 1601,
971/cm.
Example 33
(5Z)-2-decarboxy-la,lb-dihomo-5-fluoro-2-formyl-3-oxa-
18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carba-
prostaglandin-I2
Analogously to Example 25, 0.38 g of the title
15 compound is obtained in the form of a colourless
oil from 0.7 g of 2-~(Z)-(lS,5S,6R,7R)-7-(tetrahydro-
pyran-2-yloxy)-6-[(E)-(3R)-4,4-dimethyl-3-(tetrahydro-
pyran-2-yloxy)-non-1-en-5-ynyl]-bicyclol3.3.0~octan-3-
ylidene¦-2-fluoroethan-1-ol.
20 IR: 3610, 3400 (broad), 2965, 2930, 2870, 2730, 1730,
1601, 970/cm.
., .
12~85~5
Example 34
(5_)-la,lb-dihomo-5-fluoro-3-oxa-18,18,19,19-tetradehydro-
16,16,20-trimethyl~6a-carbaprostaglandin-I2
Analogously to Example 2, 0.16 g of (5Z)-la,lb-
dihomo-5-fluoro-3-oxa-18,18,19,19-tetradehydro-16,16,20-
trimethyl-6a-carbaprostaglandin-I2 11,15-diacetate
is obtained from 0.3 g of the aldehyde manufactured
according to Example 33.
After splitting off the protecting groups, 0.12 g
of the title compound is obtained in the form of
a colourless oil.
IR: 3610, 3400 (broad), 2965, 2868, 1720, 1602, 971/cm.
Example 35
(5Z)-(16RS~-2-decarboxy-13,14-didehydro-la,lb-dihomo-5-
fluoro-2-formyl-16-methyl-3-oxa-18,18,19,19-tetrade-
hydro-6a-carbaprostaglandin-I2
Analogously to Example 25, 0.2 g of the title
compound is obtained in the form of a colourless
oil from 0.41 g of 2-~(Z)-(lS,5S,6S,7_)-7-(tetrahydro-
20 pyran-2-yloxy)-6-[(3S,4RS)-4-methyl-3-(tetrahydropyran-
2-yloxy)-octa-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidene}-
5-fluoroethan-1-ol.
IR: 3600, 3410 (broad), 2966, 2731, 2224, 1727/cm.
'
~ 12~ 5
-~r~ 0
Example 36
(5Z)-(16RS)-13,14-didehydro-la,lb-dihomo-5-fluoro-16-
methyl-3-oxa-18,18,19,19-tetraaehydro-6a-carbaprosta-
glandin-I2
Analogously to Example 2, 0.1 g of (5Z)-(16RS)-
13,14-didehydro-la,lb-dihomo-5-fluoro-16-methyl-3-oxa-
18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2
11,15-diacetate is obtained from 0.2 g of the aldehyde
manufactured according to Example 35. ,
After splitting off the protecting groups, 70 mg
of the title compound are obtained in the form of
a colourless oil.
IR: 3620, 3400 (broad), 2965, 2870, 2225, 1620/cm.
Example 37
(5Z)-(16RS)-2-dec2rboxy-13,1g-didehydro-la,lb-dihomo-
16,20-dimethyl-5-fluoro-2-formyl-3-oxa-18,18,19,19-
tetradehydro-6a-carbaprostaglandin-I2
Analogously to Example 25, 0.38 g of the title
compound is obtained in the form of a colourless
20 oil from 0.7 g of 2-~(Z)-(lS,5S,6S,7R)-7-(tetrahydro-
pyran-2-yloxy)-6-1(3S,4RS)-4-methyl-3-tetrahydropyran-
2-yloxy)-nona-1,6-diynyl)-bicyclo[3.3.0]octan-3-ylidene3-
2-fluoroethan-1-ol.
IR: 3600, 3400 (broad), 2968, 2730, 2225, 1728/cm.
iZ9~35~S
Example 38
(5Z)-(16RS)-13,14-didehydro-la,lb-dihomo-16,20-dimethyl-
5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprosta-
glandin-I2
Analogously to Example 2, 0.18 g of (5Z)-(16RS)-
13,14-didehydro-la,lb-dihomo-16,20-dimethyl-5-fluoro-3-
oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2
11,15-diacetate is otbained from 0.35 g of the aldehyde
manufactured according to Example 37. 1
After splitting off the protecting groups, 0.14 g
of the title compound is obtained in the form of
a colourless oil.
IR: 3600, 3420 (broad), 2966, 2870, 2226, 1718/cm.
Example 39
(5Z)-2-decarboxy-13,14-didehydro-la,lb-dihomo-5-fluoro-
2-formyl-20-methyl-3-oxa-18,18,19,19-tetradehydro-
16,16-trimethylene-6a-carbaprostaglandin-I2
Analogously to Example 25, 0.7 g of the title
compound is obtained in the form of a colourless
20 oil from 1.2 g of 2-~(Z)-(lS,5S,6S,7R)-7-(tetrahydro-
pyran-2-yloxy)-6-l(3S)-3-(tetrahydropyran-2-yloxy)-4,4-
trimethylenenona-1,6-diynyl]-bicyclo[3.3.0]octan-3-
; ylidene3-2-fluoroethan-1-ol.
IR: 3620, 3420 (broad), 2970, 2731, 2224, 1730/cm.
, . .
.
, lZ48S25
,~
Example 40
.
(SZ)-13,14-didehydro-la,lb-dihomo-5-fluoro-20-methyl-3-
oxa-18,18,19,19-tetradehydro-16,16-trimethylene-6a-
carbaprostaglandin-I2
Analogously to Example 2, 0.31 g of (5Z)-13,14-
didehydro-la,lb-dihomo-5-fluoro-20-methyl-3-oxa-
18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-
prostaglandin-I2 11,15-diacetate is obtained from 0.6 g of
the aldehyde manufactured according to Example 39.
After splitting off the protecting groups, 0.25 g
of the title compound is obtained in the form of
a colourless oil.
IR: 3620, 3425 (broad), 2968, 2870, 2225, 1720/cm.
Exam~le 41
(5Z)-2-decarboxy-13,14-didehydro-la,lb-dihomo-16,16-
dimethyl-5-fluoro-2-formyl-3-oxa-18,18,19,19-tetra-
dehydro-6a-carbaprostaglandin-I2
Analogously to Example 25, 0.65 g of the title
compound is obtained in the form of a colourless
oil from 1.4 g of 2-~(Z)-(lS,5S,6S,7R)-7-(tetrahydro-
pyran-2-yloxy)-6-1(3S)-4,4-dimethyl-3-(tetrahydropyran-
2-yloxy)-octa-1,6-diynyl]-bicyclo[3.3.0]octa~-3-
ylidene~-2-fluoroethan-1-ol.
IR: 3600, 3420 (broad), 2970, 2930, 2865, 2730 2225,
; 25 1730/cm.
lZ~8S~5
~.
3 -
Example 42
(5Z)-13,14-didehydro-la,lb-dihomo-16,16-dimethyl-5-
fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprosta-
glandin-I2
-
Analogously to Example 2, 0.22 g of (5Z)-13,19-
didehydro-la,lb-dihomo-16,16-dimethyl-5-fluoro-3-oxa-
18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2
11,15-diacetate is obtained from 0.4 g of the aldehyde
manufactured according to Example 41. ~
After splitting off the protecting groups, 0.18 g
of the title compound is obtained in the form of
a colourless oil.
IR: 3600, 3420 (broad), 2970, 2870, 2224, 1718/cm.
Example 43
(5Z)-2-decarboxy-13,14-didehydro-la,lb-dihomo-5-fluoro-
2-formyl-3-oxa-18,18,19,19-tetradehydro 16,16,20-
trimethyl-6a-carbaprostaglandin-I2
Analogously to ExaTnple 25, 0.3 g of the title
compound is obtained in the form of a colourless
20 oil from 0.7 g of 2-~(Z)-(lS,5S,6S,7R)-7-(tetrahydro-
pyran-2-yloxy)-6-[(3S)-4,4-dimethyl-3-(tetrahydropyran-
2-yloxy)-nona-1,6-diynyl]-bicyclo[3.3.0]octan-3-
ylidene~-2-fluoroethan-1-ol.
IR: 3600, 3420 (broad), 2968, 2932, 2864, 2730, 2225,
1730/cm.
.
.~ . .
i2485ZS
55~
Example 44
(5Z)-13,14 didehydro-la,lb-dihomo-5-fluoro-3-oxa-
18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carba-
prostaglandin-I2
Analogously to Example 2, 0.14 g of (5Z)-13,14-
didehydro-la,lb-dihomo-5-fluoro-3-oxa-18,18,19,19-
tetradehydro-16,16-20-trimethyl-6a-carbaprostaglandin-I2
11,15-diacetate is obtained from 0.3 g of the aldehyde
manufactured according to Example 43. 1
Arter splitting off the protecting groups, 0.1 g
of the title compound is obtained in the form of
a colourless oil.
IR: 3605, 3420 (broad), 2970, 2870, 2225, 1720/cm.
Example 45
(5E)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-
tetradehydro-6a-carbaprostaglandin-I2 methyl ester
An ethereal diazomethane solution is added dropwise
at 0C to a solution of 60 mg of (5E)-(16RS)-la,lb-
dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-
20 carbaprostaglandin-I2 in 10 ml o_ dichloromethane
until a constant yellow colouring is obtained. After
S minutes the whole is concentrated by evaporation
in vacuo and the residue is chro~,atographed over
silica gel. Vsing ethyl acetate~hexane (4~1), 40 mg
~'"`` '' .
.
~ 12~8525
of the title compound are obtained in the form of
a colourless oil.
IR: 3600, 3400 (broad~, 2960, 1740, 974/cm.
Example 46
(SE)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19- -
tetradehydro-6a-carbaprostaglandin-I2 carboxamide
lOS mg of (5E)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-
18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2
are dissolved in 3 ml of tetrahydrofuran; 40 mg
10 of triethylamine and 45 mg of chloroformic acid isobutyl
ester are added at 0C. After 1 hour, ammonia gas
is introduced at 0C for 10 minutes and then the
whole is left to stand for 1 hour at 24C. The mixture
is subsequently diluted with 30 ml of water, extracted
15 three times with 30 ml of methylene chloride each
time, and the combined organic extracts are shaken
with 20 ml of brine, dried over magnesium sulphate
and concentrated by evaporation in vacuo. Chromato-
graphy of the residue over silica gel with methylene
: 20 chloride/isopropanol (9+1) yields 78 mg of the title
compound in the form of an oil.
~ ~IR: 3610, 3540, 3400 (broad), 2960, 1670, 975/cm.
:'
...
`' ~"- . ..
:
12~ 5
Example 47
(5Z)-(16RS)-la,lb-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-
tetradehydro-6a-carbaprostaglandin-I2(2,3-dihydroxypropyl)-amide
195 mg (5Z~-( 16RS ) -la, lb-dihomo-5-fluoro-16-methyl-3-
oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 are
dlssolved in 5 ml of aceton; 60 mg of triethylamine and 75 mg of
chloroformic acid isobutyl ester are added at 0C. After 20
minutes, a solution of 260 mg of 1-amino-2,3-dihydroxypropane in
8 ml of aceton and 8 ml of acetonitrile are added and stirring is
carried out for 2 hours at 20C. The whole is concentrated in
vacuo, diluted with methylene chlorlde, shaken with a little
brine and the organic phase is dried over magnesium sulphate and
concentrated by evaporation in vacuo. Chromatography of the
residue over silica gel with methylene chloride/isopropanol (8+2)
yields 160 mg of the title compound in the form of a colourless
oil. IR: 3600,3400 (broad), 2935,1645,974/cm.
Exam~le 48
(5Z)-~16RS)-la,lb-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-
tetradehydro-6a-carbaprostaglandin-I2(4-phenyl)-phenacyl ester
120 mg of (5z)-(l6Rs)-la~lb-dihomo-5-fluoro-l6
- 59 -
X
2~ 5
methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprosta-
glandin-I2 are dissolved in 3 ml of acetone; 90 mg
of ~-bromo-4-phenylacetophenone and 1 ml of triethylamine
are added and stirring is carried out overnight at
room temperature. 100 ml of ether are added and
the whole is shaken twice with 10 ml of water each
time, dried over magnesium sulphate and concentrated
by evaporation in vacuo. Purification is carried
out by preparative thin-layer chromatography on silica
gel plates which are developed with ethyl acetate.
128 mg of the title compound are obtained.
IR: 3610, 2940, 1740, 1703, 1602, 974/cm.
Example 49
~5E)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-
15 tetradehyd~o-6a-carbaprostaglandin-I2 tris-~hydroxy-
methyl)-aminomethane salt
-
A solution of 60 mg of tris-(hydroxymethyl)-amino-
methane in 0.2 ml of water is added at 70C to a
solution of 185 mg of (5E)-(16RS)-la,lb-dihomo-16-methyl-
20 3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2
in 35 ml of acetonitrile. The whole is cooled while
stirring, the solvent is decanted off after 16 hours
and the residue is dried ln vacuo. 160 mg of the
title compound are isolated in the form of a wax-like
25 substance.
