Note: Descriptions are shown in the official language in which they were submitted.
g~
BACKGROUND OF INVENTION
The present invention relates to certain novel organic
compounds. In particular this invention relates to
certain novel 3-oxaprostaglandin derivatives of Formula
VII. In addition, this invention relates to certain
trialkylsilyl intermediates of Formula VIII.
The novel compounds of the present invention display
valuable pharmacological properties as is exemplified by
their ability t~ inhibit the gastric secretion stimulated
by secretogogues such as histamine and pentagastrin. In
addition, these compounds possess the remarkable ability
to protect the gastric and intestinal mucosa against the
damaging effects of such agents as ethanol and Aspirin.
This effec-t has been termed "cytoprotection~ ~see A.
Robert et al., Gastroenterology, 77, 433 (1979~).
Furthermore~ these compounds have the surprising advantage
of substantially decreased undesirable side effects such
as diarrhea and uterine sti~ulant activity displayed by
related substances. The gastric antisecretory activity is
determined by standard laboratory means.
Gastric antisecretory agents may be used to treat such
diseases as hypersecretion of gastric acid and peptic
ulcer. A number of methods to control these conditions
exist including, gastric antacids, antimuscarinic drugs,
H2-receptor blockers and prostaglandins lPG). Goodman
and Gilman, Sixth Ed., 1980, pgs. 997, 632, 995-997 and
678.
-2-
* Trade Mark
~9~99~
PG analogs are all known to cause side effects,
notably diarrhea. However, the capacity to suppress
gastric secretion by these compounds is well documented.
Prostanoic acid is well known and has the structure
and numbering as follows.
9 7 s 3
,_~ ",~_ " ~ " COOH
o < II
\ ~ 14 16 18
~ ~ ~ 20
ll l3 15 17 19
The compounds are more particularly derivatives of
PGE2. For background on prostaglandins, see for example
Bergstrom _ al., Pharmacol. Rev. 20, 1 (1968).
PRIOR ART
Derwent abstract 60337V/34 corresponding to German
Offenlegungsschrift 2,406287 depicts 3-oxaprostaglandins
of the E2 series, specifically as 15-hydroxy compounds.
SUMMARY OF THE INVENTION
The present invention particularly provides a compound
accordin~ to formula:
+) ~ ~ 2 n\ ~ ~ R3 VII
HO` ~ R2
~2~3;294
Wherein Rl is:
a) hydrogen;
b) alkyl of 1 to 6 carbon atoms, inclusive;
c) trifluoromethyl;
d) trichloromethyl;
e) alkenyl; or
f) alkynyl;
wherein R2 is straight chain alkyl of 1 to 6 carbon
atoms inclusive;
wherein R3 is:
a) -COOR4
b) ~CH20H; or
c) -C(o)CH20Hi
wherein R4 is alkyl of 1 to 6 carbon atoms inclusive
and wherein n is an integer of from 1 to 6 inclusive.
In addition the invention also relates to novel
intermediates of the formula:
OSi(alkyl)3
(~) ~ (CH2)n~=~
~ OSi(alkyl)3
(alkyl)3SiO` ~ R2
1 VIII
Where n, Rl and R2 are as described above and
alkyl relates to.alkyl of 1 to 6 carbon atoms inclusive.
Fxamples o alkyl l to 6 carbon atoms, inclusive, are
methyl, ethyl, propyl, butyl, pentyl and hexyl and
isomeric forms thereof.
Also included in the invention are the individual
stereoisomers, and mixtures of the isomers.
Optional bonds are indicated as dashed lines.
Further, alpha configurations are represented by a
hatched line, and beta configurations are represented by a
solid line, in all formulas.
The specific assay used to detect gastric
antisecretory activity is described as follows:
Adult female beagle dogs weighing 13-20 kg are
prepared with denervated fundic Heidenhain pouches. After
a recovery period of at least 4 weeks following surgery,
the animals are fasted for approximately 20 hours, then
are placed in Pavlov stands and infused intravenously with
saline solution. The pouched secretions are collected
every 15 minutes and measured for volume and total acidity
by titration with O.lN sodium hydroxide to pH 7Ø
Following a 30 minute basal secretion the dogs are infused
with a saline solution of histamine dihydrochloride at a
dose of 1.0 mg/hr. The volume of the diffusion is kept at
approximately 13 ml/hr. A steady state plateau of gastric
secretion is obtained approximately 1 hour following the
start of histamine infusion, at the end of which time the
test compound dissolved i~ an ethanolic iso-osmotic
phosphate buffer solution is administered by a single
intravenous injec-tion. The duration of the anti-secretory
2~29D~
effects is determined and the side-effects, if any,
recorded. The compound is rated active if statistically
significant inhibition of secretory parameters occur
following compound treatment.
Cytoprotective activity is tested as follows. Male,
Charles River rats, weighing 180 to 220g, which are food
deprived for 24 hours are administered a test compound.
Thirty minutes later, each rat is given 1.0 ml of absolute
ethanol intragastrically. The rats are sacrificed sixty
minutes after alcohol administration and gastric mucosae
are visually examined for the presence of lesions.
Objective scoring is based on the presence or absence of
lesions and data recorded as the n~lmber of rats per group
completely protected from lesion formation.
Compounds of this invention were tested as above and
found to be antisecretory and cytoprotective. By virtue
of these activities, the compounds of Formula VII are
useful in treating and alleviating gastric ulcers in
mammals.
The compounds of the present invention are formulated
into pharmaceutically acceptable dosage forms by
conventional methods known to the pharmaceutical art. For
example, the compounds can be administered in oral unit
dosage forms such as tablets, capsules, pills, powders, or
granules. They also may be adminis-tered rectally or
vaginally in such forms as suppositories or bougies; they
may also be introduced in the form of eye drops,
intraperitoneally, subcutaneously, or intramuscularly,
94
using forms known to the pharmaceutical art. In general
the preferred form of àdministration is oral.
An effective but non-toxic quantit~ of the compound is
employed in treatmentO The dosage regimen for preventing
or treating symptoms by the compounds of this invention i5
selected in accordance with a variety of factors including
the type, age, weight, sex, and medical condition of the
marnmal, the severity of the symptoms, the route of
administration and the particular compound employed. An
ordinarily skilled physician or veterinarian will readily
determine and prescribe the effective amount of the agent
to prevent or arrest the progress of the condition. In so
proceedingt the physician or veterinarian could employ
relatively low dosages at first, suhsequently increasing
the dose until a maximum response is obtained.
Initial dosages of the compounds of the invention are
ordinarily in the area of 0.25 ~g/kg up to at least
50 ~g/kg orally. When other forms of adrninistration are
employed equivalent doses are administered.
The compounds of this invention can also be administered
as pharmacologically acceptable alkali metal salts such as
lithium, sodium and potassium and the like, and hydrates
thereof.
The compounds of Formula VIII are useful in preparing
compounds of Formula VII.
The compounds of this invention are prepared by the general
methods illustrated in the accompanying Charts A through F on
pages 31 to 36. Chart A on page 31: Furfural, Formula I, re-
acts with omega-alkynyl rnagnesium halides, Grignard reagents
prepared by methods known to those skilled in the art from
--7--
2~
omega-haloalk-l-ynes, II, to form the intermediate compounds
of Formula III. Where n is greater than 1, the acetylene
group of the Grignard is protected by a trialkylsilyl group
that can later readily be removed by aqueous po-tassium
fluoride treatment. Where n is 1, R may be hydrogen and no
deprotection is necessary to yield compound III. Preferred
reaction conditions include addition at ca. 0~ of a
tetrahydrofuran solution of compound I to a diethyl ether
solution of the freshly prepared Grignard reagent. Compounds
III are typically purified by distillation at reduced
pressure. The intermediates III rearrange upon heating under
acidic conditions to form cyclopentenyl compounds of Formula
IV. Preferred conditions include heating at ca. 80-85 in
aqueous dioxane containing ~-toluenesulfonic acid. Crude
compounds IV are typically purified by extraction and column
chromatography on silica gel. Compound III further
rearran~es under acidic or basic conditions to form the
isomeric compounds of Formula V. Preferred conditions
include treatment of compounds IV with basic Grade III
alumina at room temperature. Protection of alcohol
intermediates V, using a protecting group (R1o) such as
trialkylsilyl or tetrahydropyranyl by reaction in an inert
organic solvent affords the protected derivatives, Formula
VI. Preferred reagents and conditions include triethylsilyl
:, ;
chloride and imidazole in dimethylformamide at room
temperature. The intermediate compounds VI are typically
purified ~y column chromatrography on silica gel.
~2~299~
Chart B on page 32: Compounds VI react first with organo-
copper reagents, Formula XI (prepared by the general method
described in U.S. Patent 4,271,314) and then with suitable
silylat~ng reagent to form intermediates of Formula XII.
Preferred conditions include reaction of VI and XI at ca.
-60 in diethyl ether, followed by addition of a trialkyl
silyl chloride, preferably with at least one bulky alkyl
group (e.g. t-butyldimethylsilyl chloride) which will
increase yields and stability, and hexamethylphosphoric
triamide, with warming to ca. -20. ~fter extracting
into an organic solvent, such as diethyl ether, and
stripping volatiles, the crude intermediates XII are
typically purified by column chromatography on silica
gel. The acetylenic intermediates XII, after treatment
with a strong nonaqueous base in an inert organic solvent,
react with dry paraformaldehyde to form isolable
intermediates which in turn may be treated with alkyl
haloacetates to form intermediates of Formula XIII.
Preferred conditions include reaction of XII with
butyllithium in tetrahydrouran at ca. -20, followed
next by addition of paraformaldehyde, and then by addition
of alkyl bxomoacetates and hexamethylphosphoric triamide.
Intermediates XIII are typically purified by column
chromatography on silica gel. Hydrolysis of protected
compounds XIII under acidic conditions affords acetylenic
compounds of this invention, Formula XIV. Preerred
hydrolytic conditions include a 3:1:1 mixture of acetic
acid/tetrahydrofuran/water stirred at room temperature
_g_
~2~9~
initially and then warmed to ca. 45-50. Acetylenic
compounds XIV are typically purlfied by column chroma-
tography on silica gel.
Analogous alkenyl compounds of this invention, Formula
XV, are prepared by catalytic hydrogenation of compounds
XIV, using such catalysts as palladium, platinum, ruth-
enium, and rhodium which have been suitably attenuated
or Raney Nickel. Preferred reduction conditions employ
hydrogen at atmospheric pressure, cyclohexane/toluene
containing quinoliner and 5% palladium/calcium carbonate
cataiyst. Alkenyl compounds XV are typically purified by
column chromatography on silica gel.
An alternative conversion of intermediate XIII to
alkenyl compounds XV is illustrated in Chart C on page
33: Compound XIII is initially hydrogenated by the gen-
eral method described in Chart B. Hydrogenation conditions
are similar, except that the pr~ferred catalyst is 5%
palladium~barium sulfate. Hydrolysis of resultant
intermediates, Formula XXI, under acidic conditions
affords alkenyl compounds XV. Preferred hydrolytic
conditions include a 3:1:1 acetic acid/tetrahydrofuran/
water mixture.
The carboxylate function of acetylenic or alkenyl com-
pounds of Formulas XIII and XXI may be reduced to corres-
ponding alcohol functions, as illustrated in Chart D on
page 34. Reductions are effected with any of various ac-
tive metal hydrides by methods known to those skilled in
the art. Preferred conditions include reaction at ca. 0
--10--
~z~
with lithium aluminum hydride in diethyl etherO Silyl
protecting groups are removed by hydrolysis under acidic
conditions, preferably 3:1:1 acetic acid/tetrahydrofuran/
water, giving compounds of Formula XXXI. The compounds
are typically puri~ied by column chromatography on silica
gel.
Charts E and F, on pages 35 and 36 respectively, il-
lustrate methods for preparing hydroxymethylketone ana-
logs from the furan întermediate III (wherein n is 1) des-
cribed above. (See Chart A). Chart E: The hydroxyl func~tion of III is prote~ted with an acid-labile group for sub-
sequent reactions. A preferred protecting group is tetra-
hydropyranyl, added to compounds III by reaction with di-
hydropyran under acidic conditions-by methods known to
those skilled in the art. The protected intermediate i5
converted to acetylenic intermediates XLI by reactions
first with paraformaldehyde in strongly basic medium and
then with alkyl haloacetates, as described above. (See
Chart B). Corresponding alkenyl intermediates, Formula
XLII, are prepared by catalytic reduction of acetylenic
compounds XLI, as described above. (See Charts B and C).
A prefexred hydrogenation catalyst is 5% palladium/calc$um
carbonate.
Chart F: Rearrangements of acetylenic or alkenyl
compounds, Formulas XLI and XLII, to cyclopentenyl
compounds, Formula LI, are effected by the same general
methods used to convert compound III to compound V,
described above. (See Chart A). The preferred basic
conditions for the second rearrangement, however, employ
~2~9~
aqueous sodium carbonate containing a small guantity of
hydroquinone. Reaction of intermediates LI with a
hindered trialkylsilyl halide, preferably
t-butyldimethylsilyl chloride, affords intermediates of
Formula LII. The ester function of LII is converted to
the hydroxymethylketone function of LIII by the general
method described by A. Wissner, J. Org. Chem., 44,
4617 (1979~. Intermediates LII, are converted to the
corresponding acyl halides, preferably by reaction with
oxalyl chloride and dimethylformamide in an inert organic
solvent such as dichloromethane. The unisolated acyl
halides react with tris(trimethylsilyloxy)ethylene to form
unisolated intermediates which, upon heating in acidic
medium, hydrolyze and decarboxylate to intermediate
alcohols LIII, which are typically purified by column
chromatography on silica gel. Silylation of compounds
LIII affords protected compounds, Formula LIV. Preferred
silylation conditions include reaction of LIII with
triethylsilyl chloride in dimethylformamide containing
imidazole. Reaction of intermediates LIV with
organocopper compounds of Formula XI as described above
(See Chart B.), followed by hydrolysis, preferably using
3:1:1 acetic acid/ tetrahydrofuran/water as described
above (See Chart B.), affords hydroxymethylketone
compounds of this invention, Formula LV. Compounds LV are
typically purified by column chromatography on silica ge~.
-12-
9~
DESCRIPTION OF THE PREFE~RED EM~ODIMENTS
EXAMPLE l
Preparation of ~-(2-propynyl)-2-furanmethanol
Propargyl magnesium bromide was prepared by adding a
solution of propargyl bromide (as 145.5 g of 80%, by
weight, solution in toluene; 0.976 mole) in 150 ml of
diethyl ether to a slurry of 26 g (1.07 mole) of
iodine-acti.vated magnesium and 340 mg of mercuric chloride
in 450 ml of ether. The rate of addition was adjusted to
maintain a vigorous reflux. After addition was complete,
the reaction mixture was stirred at room temperature for
one hour and then cooled to 0. A solution of 75 g (0.78
mole) of 2-furancarboxaldehyde in 400 ml o
tetrahydrofuran was added dropwise, and the reaction
mixture was stirred at room temperature for fifteen
minutes, then poured onto a cold saturated ammonium
chloride solution and stirred vigorously. The layers were
separated and the a~ueous layer was extracted with ether.
The organic phase was washed with saturated ammonium
chloride solution and with brine, dried over sodium
su3fate, filtered, and concentrated to dryness.
Distillation of the crude material at 1.0 torr gave 100.6
g of the title compound, b.p.68-72. Structure assignment
was confirmed by the proton nmr spectrum: 2.05 (t, J =
2-3 HZ, - C-H), 2.59 (d of d, J = 2-3 and 5-6 Hz,
-CH2-C-), 4.80 (q, J = 5-6 Hz, -CHOH-), 6.27 and 7.32
ppm (furan).
-13-
~2~9~
~3`
o ~
OH
EXAMPLE 2
4-hydroxy-2-(2-propynyl)-2-cyclopenten-1-one
To a solution of 40.2 g (0.295 mole) of the title
compound of Example l in 800 ml of a 8:1 dioxane/water
mixture was added 4 g (0 21 mole) of ~-toluenesulfonic
acid. The reaction mixture was heated at 83 for 36 hours
under argon, cooled, and diluted with 500 ml of ethyl
acetate. The organic phase was washed once with water and
two times each with 5% sodium bicarbonate solution and
brine solution. The aqueous washes were combined and
extracted with ethyl acetate. The combined organic phases
were dried over sodium sulfate, filtered, and
concentrated. Chromatography of the combined crude
materials on silica gel (using 25% ethyl acetate in hexane
as eluent) gave 12.45 g of the intermediate compound
4-hydroxy-5-(2-propynyl)-2-cyclopenten-1-one as a viscous
oil. Structure assignment was confirmed by the proton nmr
spectrum.
A solution of 14.5 g (0.11 mole) of the cyclopentenone
intermediate in 50 ml of ether was poured into a column
packed with 282 g of Grade III alumina (6% water by
weight). The column was closed and allowed to stand at
-14-
room temperature for twenty four hours. The product was
elu~d ~rom the column with ether and ethyl acetate to
give 7.3 g of the title compound as a viscous oil.
Structure assignment was confirmed by the proton nmr
spectrum: 7.5 (mult, = C ~ ), 4.98 (-CHOH), 2.16 (t, J
= 2-3 Hz, - C-H), 3.07 ppm (mult, J -CH2 -C_).
HO
EXAMPLE 3
2-(2-propynyl)-4-l(triethylsilyl)oxy~-2-cyclopente~-1-one
A solution of 250 mg ~1.84 mmole~ of the title
compound of Example 2 in 4 ml of dimethylformamide was
treated successively with 200 mg (3 mmole) of imidazole
a~ 3~ mg ~2 mm~le~ Df triethy~si~y~ ch}Dri~e, A~er
stirring for thirty minutes, the reaction mixture was
diluted with ether, washed with water, dried over sodium
sulfate, filtered, and concentrated to dryness. The crude
material was chromatographed on silica gel to give 0.37 g
of the title.compound as an oil. Structure assignment was
c~n}rme~ by ~he pro~on nmr spec~r~m~ t, ~ Z,
- C-~, 3.08 (mult, -CH2-C-), 4.~0 (mult, C-ll~,
7.35 ppm (=C~ ).
-15-
oSiEt3
EXAMPLE 4
(l,l-dimethylethyl)dimethyl[[3~-[4-methyl-
4-[(trimethylsilyl)oxy]-lE-octenyl]-2-(2-propynyl)-4~-
~(triethylsilyl)oxy]-l-cyclopenten-l-yl~ oxy]silane
A solution of 10 g (0.02 mole) trimethyl[l-methyl-
1-[3-(tributylstannyl)-2E-propenyl]pentoxy]silane in ~5 ml
of tetrahydrofuran was cooled to -60 under an argon
atmosphere, and 11.8 ml of a 1.7 M solution of
n-butyllithum in hexane (0.02 mole) was added. The
reaction mixture was stirred for forty five minutes, after
which a solution of 2.62 g (0.02 mole~ of copper-l-pentyne
and 6.4 g (0.04 mole) of hexamethylphosphorus triamide in
75 ml of ether was added dropwise. After ten minutes, a
solution of 2.4 g (0.01 mole) of -the title compound of
Example 3 in 20 ml of e-ther was added, and the reaction
mixture was stirred an additional 45 minutes~ A solution
of 3 g (0.02 mole) of t-butyldimethylsilyl chloride in 1
ml of ether was added, followed by the addition of 25 ml
of hexamethylphosphoric triamide. The temperature was
allowed to rise to -20~, where it was maintained for one
hour. The reaction mixture was poured into 1 N
hydrochloric acid and ~ther. The layers were separated
- 1 S -
and the organic phase was washed with water, dried over
sodium sulfate, filtered, and concentrated to dryness.
The crude material was chromatographed on silica gel to
give 4 g of the title compound as a viscous oil.
Structure assignment was confirmed by the proton nmr
spectrum: 1.80 (t, J = 1-2 Hz, - C-H), 4 . 95-5 . 80
(mult, C-13, 14), 0.90 ppm (t-Bu).
tBu
OSi -Me
~Me
~ CH3
OSiEt3 OSiMe3
EXAMPLE 5
methyl [[4-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy~-
5~-[4-methyl-4-[(trimethylsilyl)oxy~-lE-octenyl]-
4a-~ (triethylsilyl)oxy]-1-cyclopenten-1-yl]-
2-butynyl]oxy3acetate
A solution of 434 mg (0.75 mmole) of the title
compound of Example 4 in 5 ml of tetrahydrofuran was
cooled to -20 under a nitrogen atmosphere, and 0.49 ml of
a 1.7 M solution of n butyllithium in hexane (0.83 mmole)
was added After stirring for one hour at -20, 27 mg
(0.89 mmole) of solid, dried paraformaldehyde was added,
and the reaction mixture was warmed to 0. After stirring
for ninety minutes at 0, the reaction mixture was
recooled to -20, and 147 mg (0.96 mmole) of methyl
bromoacetate and 1 ml of hexamethylphosphoric triamide
~æ~
were added. The reaction mixture was stirred at -20 for
75 minutes, then allowed to warm to room temperature
before being poured onto 45 ml of water. The product was
extracted into ether, which was then washed with brine,
dried over sodium sulfate, filtered, and concentrated to
dryness. Chromatography of the crude material on silica
gel afforded 90.7 mg of the title compound. Structure
assignment was confirmed by the proton nmr spectrum: 0.95
(t-Bu)~ 1.42 (C-16 CH3), 4.00 (C-ll), 4.15 (C-2), 4.25
(C-4), 3.75 ppm (MeO).
tBu
OSi - Me
Me
~ 0~ C02CH3
oSiEt
OSiMe3
;
EXAMPLE 6
methyl[[4-[3a-hydroxy-2~-(4 hydroxy-4-methyl-lE-octenyl)
-5-oxo-1~-cyclopentyl]-2-butynyl]oxy]acetate
A mixture of 106 mg (0.17 mmole) of the title compound
of Example 5 in 8 ml of a 3:1:1 solution of acetic acid/
tetrahydrofuran/water was stirred at room temperature for
four hours and heated at 45-50 for 1 hour. The reaction
mixture was poured onto 80 ml of water and extracted with
ether. The organic phase was washed with water, 5% sodium
bicarbonate solution, again with water, dried over sodium
sulfate, filtered, and concentrated to dryness. The crude
material was chromatographed on silica gel to yield 21.3
-18-
~z~
mg of the title compound as an oil. Structure assignment
was confirmed by the proton nmr spectrum: 0.92 (C-20),
1.19 (C-16 CH3), 3-75 (-OCH3~, 4.15 (C-2), 4.25 ~C-4),
4.00 (mult, C-ll), 5.15-6.00 ppm (mult, C-13, 14).
~ ~` \ ~ O ~ C2CH3
HO`
OH
EXAMPLE 7
l,l-dimethylethyl-
I[4-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-
5~-[4-methyl-4-[(trimethylsilyl)oxy]-lE-octenyl]-
4~-[(triethylsilyl)oxy]-1 cyclopenten-1-yl]-
2-butynyl]oxy]acetate
The title compound was prepared by the method of
Example 6 using 611 mg (1.06 mmole) of the title compound
of Example 4 in a mixture of 10 ml of tetrahydrofuran,
0.75 ml (1.28 mmole) of n-butyllithium solution, 36 mg
(1.19 mmole~ of paraformaldehyde, 215 mg (1.10 mmole) of
t-butyl bromoacetate and 1 ml of hexamethylphosphoric
triamide. Chromatography of the crude material on silica
gel gave 151 mg of the pure title compound and 149 mg of
slightly impure compound which was used for subse~uent
reactions without further purification. Structure
assignment was confirmed by proton nmr spectrum: 0.92
--19--
~2~Z9~
(Si-t-Bu), 1.48 (-0-t-Bu), 1.18 (C-16 CH3), 4.03 (C-2),
4.23 ppm (C-4).
tBu
osi - Me
¦ ~Me
~0~ C02t-BU
\ / CH
EXAMPLE 8 1,1-dimethylethyl-[[4-[3a-hydroxy-2~-
(4-hydroxy-4-methyl-lE octenyl)-5-oxo l~-cyclopentyl]-
2-butynyl]oxy]acetate
The title compound was prepared by the method of
Example 6 using 63 mg (0.092 mmole) of the title compound
of Example 7 in ~ ml of the 3:1:1 acetic
acid/tetrahydrofuran/water solution. An additional 2 ml
of the acetic acid/tetrahydrofuran/water solution was
added after twenty four hours and the reaction mixture was
heated at 45-50~ for one hour. The reaction mixture was
concentrated and diluted with ether. The organic phase
was washed with water, 5% sodium bicarbonate solution, and
water, then dried over sodium sulfate, filtered, and
concentrated to dryness. Chromatography of the crude
material on sil1ca gel afforded 15 mg of the title
compound. Structure assignment was confirmed by the
proton nmr spectrum: 0.90 (C-20), 1.15 (C-16 CH3), 1.45
~t-Bu), 3.98 (C-2), 4.20 ppm (C-4).
-20-
~ 02t~Bu
HO
OH
EXAMPLE 9
methyl [l4-l2-[[1,1-dimethylethyl)dimethylsilyl]oxy]-
5B-14-methyl-4-ltrimethylsilyl)oxy]-lE-octenyl]
4a-[ (triethylsilyl)oxy]-1-cyclopenten-1-yl3-
2Z-butenyl~oxy]acetate
A solution of 83 mg (0.13 mmol) of the title compound
of Example 5 in 50 ml of toluene, to which had been added
O.9S ml of 5% quinoline in toluene, was hydrogenated at
atmospheric pressure and room temperature over 5%
palladium/barium sulfate catalyst. After filtration the
reaction mixture was concentrat~d to an oil containing
residual quinoline. The title compound exhibited the
expected proton nmr spectrum and was used without further
purification: 0.89 (Si-t-Bu), 1.15 (C-16 CH3), 3.74
(-OCH3), 4.03 (C-2), 4.15 (C-4), 5.0-5.75 ppm (C-13, 14
and 5,6).
tBu
OSi- Me
¦ Me
~ 3 ~ C02Me
OSiEt3 OSiMe3
-21
^~Z~29~
EXAMPLE lO methyl ll4-[3a-hydroxy-2~-(4-hydroxy-
4-methyl-lE-octenyl)-5-oxo-la-cyclopentyl]-
2Z-butenyl]oxy]acetate
The title compound was prepared by the method of
Example 6 using 97 mg of the title compound of Example 9
(contaminated with quinoline) and 8 ml of a 3:1:1 acetic
acid/tetra~ydrofuran/ water mixture, with stirring at room
temperature for 22 hours. The crude material was
chromatographed on silica gel to yield 31.8 mg of the
title compound as an oil. Structure assignment was
confirmed by the proton nmr spectrum: 3.7S (-OCH3),
4.10 (C-2), 1.15 (C-16 CH3), 5.15-6.0 ppm (C-13, 14, and
C-5,6).
~ __~^~o ~ CO2CH3
HO ~r~
EXAMPLE 11 1,1-dimethylethyl-[[4-[3a-hydroxy-2~-
(4-hydroxy-4-methyl-lE-octenyl~-5-oxo-la-cyclopentyl]-2Z-
butenyl~oxy]acetate
A solution of 22 mg (0.052 mmole) of the title
compound of Example 8 in 3 ml of l:l cyclohexane/toluene,
to which was added 1.8 ml of 0.1% quinoline in toluene,
was hydrogenated at atmospheric pressure at 0 using 5%
-22-
3~2~9;i~
palladium/calcium carbonate catalyst. After filtration to
remove catalyst, the reaction mixture was concentrated to
dryness. Chromatography on silica gel yielded 12.6 mg of
the title compound as an oil. Structure assi~nment was
confirmed by the proton nmr spectrum: 1.15 (C-16 CH3),
1.4S (t-Bu), 3.93 (C-2), 4.10 (d, J = 6 Hz, C-4), 5.15-6.0
ppm (mult, C-13, 14 and C-5, 6).
o~ co 2 tBU
H
OH
EXAMPLE 12 4a-hydroxy-2~-[4-~2-hydroxyethoxy)-2Z-
butenyl]-3~-(4-hydroxy-4-methyl-lE-octenyl)cyclopentanone
To a solution of 683 mg of the title compound of
Example 9 cooled to oD ~ is added 40 mg of lithium aluminum
hydride. After 15 minutes at 0, the reaction mixture is
poured into diethyl ether and water. The ether layer is
separated and washed with water, dried over sodium
sulfate, filtered and concentrated to dryness. The
residue is dissolved in 15 ml of a 3:1:1 acetic
acid/water/tetrahydrofuran mixture and stirred overnight
at room temperature. After diluting the reaction mixture
with diethyl ether, it is washed with water, dried over
sodium sulfate, filtered and evaporated to dryness.
Chromatography of the residue on silica ~ (using ethyl
acetate as eluent) gives the title compound.
-23-
0~--/
o~
OH CH3
EXAMPLE 13 4a-hydroxy-2~-[4-(2-hydroxyethoxy)-2-
butynyl]-3~-(4-hydroxy-4-methyl-lE-octenyl)cyclopentanone
The title compound is prepared by the method of
Example 12 using 68 mg of the title compound of Example 5
as starting material.
,~"~OH
\ / OH
HO
C~13
EXAMPLE 14 2-[1-(2-furanyl3-3-butynyloxy]tetrahydro-2H-
pyran
To a solution of 10 g (0.073 mole) of the -title
compound of Example 1 in 40 ml of tetrahydrofuran is added
lOg (0.12 mole) of dihydropyran and 100 mg of
p-toluenesulfonic acid monohydrate. The reaction mixture
is stirred at room temperature for 4 hours, then diluted
with water and 5 ml of 5% agueous sodium hydroxide. After
removal of the solvent, the residue is extracted three
-24-
times with diethyl ether. The organic layers are washed
with brine, dried over sodium sulfate, filtered and
concentrated to dryness. The residue is chromatographed
on silica gel (using ethyl acetate/hexane as eluent) to
give the title compound NMR: 2.78 (d of d, J = 6, 2.5 Hz,
-CH2-C_), 1.92 (t, J = 2Hz, -CH), 3.18-4.08
(mult,-CH2-0), 7.49 and 6.33 ppm (furan).
~'
~'
EX~MPLE 15 1,1-dimethylethyl-1[5-(2-furanyll-5-
I(tetrahydro-2H-pyran-2 yl)oxy]-2-pentynyl]oxy]acetate
The title compound is prepared by the method of
Example 5 using 1 g of the title compound of Example 14 in
10 ml of tetrahydrofuran, one equivalent of
n-butyllithium, 0.16 g of paraformaldehyde, 1 ml of
hexamethylphosphoric triamide, and 1.06 g of t-butyl
bromoacetate.
' ~3
O \~\0~\ C02tBu
'' ~
EXAMPLE 16 l,l-dimethylethyl [~5-(2-furanyl)-5-
(tetrahydro-2H~pyran-2-yl)oxy]-2Z-pentenyl~oxy]acetate
The title compound is prepared by the method of
Example 11 using 1 g of the title compound from Example 15
and 150 mg of 5% palladium/calcium carbonate catalyst.
o ~0~ C02tBU
0 ~
EXAMPLE 17 1[4-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)-2-
butynyl]oxy]acetic acid
The title compound is prepared by the method of
Example 2 using 1 g of the title compound of Example 15,
with the exception that the intermediate cyclDpentenone is
rearranged using a~ueous sodium carbonate solution ~p~
10-11) containing 1% hydroquinone. After stisring for Z4
hours at room temperature, the reaction mixture i~
acidified to pH 2-3 with dilute hydrochloric acid and
extracted with ether. The combined extracts are washed
with brine, dried over sodium sulfate, filtered, and
concentrated to dryness. The residue is chromatographed
on Biosil A (using ethyl acetate/hexane as eluent) to
afford the title compound.
-26-
* Trade Mark
~z~294
\ O~\C02H
HO
EXAMPLE 18 4-[(triethylsilyl)oxy]-2-[4-[2-oxo-3-
(triethylsilyl)oxy]propoxy]-2-butynyl]-2-cyclopenten-1-one
A solution of 500 mg of the title compound from
Example 17 and 600 mg of imidazole in 8 to 10 ml of
dimethylformamide is treated at room temperature with 800
mg of t-butyldimethylsilyl chloride. After 1 hour, the
reaction mixture is poured into a mixture of hexane/ether
(~:1) and water. The organic layer is washed with water
three times, dried over sodium sulfate and concentrated
in vacuo. Chromatagraphy on silica gel (using 10% ethyl
acetate/hexane as eluent) yields the intermediate product,
a bis silyl ether.
A solution of 600 mg of the silyl ether in 5 ml of
methylene chloride cooled to 0 is treated with 2-3 drops
of dimethylformamide and then with a solution of 200 mg of
oxalyl chloride in one ml of methylene chloride. The
reaction mixture is allowed to warm to room temperature
and aft~r one hour the solution is blown to dryness. The
residue is dissolved in 6 ml of chlorobenzene, treated
with 700 mg of tris(trimethylsilyloxy)ethylene prepared as
described by A. Wissner, J. Org. Chem., 44, 4617
-27-
~Z~ 9~
(1979), and refluxed under argon for 3 to 4 hours. The
mixture is cooled, concentrated to a paste which is
dissolved in 3 to 4 ml of tetrahydrofuran, and treated
with one ml of 1 N hydrochloric acid. After refluxing
under argon for one hour, the solution is cooled, diluted
with ethyl acetate, and washed with brine solution. The
aqueous wash is extracted twice with chloro~orm and the
combined extracts are dried over sodium sulfate, filtered
and concentrated to dryness. Chromatography of the
residue on silica gel (using 80% ethyl acetate/20% hexane
as eluent) gives an oil.
The oil (110 mg) is dissolved in 2 ml of
dimethylformamide containing 150 mg of imidazole and then
is treated with 150 mg of triethylsilyl chloride. The
reaction mixture is stirred at room temperature for one
hour and is diluted with diethyl ether, washed with water
three times, and then dried over sodium sulfate.
Filtration and removal of the solvent gives the title
compound.
S~/\ ~ ~\oSiEt3
OSiEt3
;
EXAMPLE 19 4-hydroxy-3~--(4-hydroxy-4-methyl lE-
octenyl~2~[4-(3-hydroxy-2-oxopropoxy)-2-butynyl
cyclopentanone
-28-
The title compound is prepared by the methods of
Examples 4 and 6 using 500mg of the title compound of
Example 18, except that the copper enolate is not trapped
with t-butyldimethylsilyl chloride but is worked up
directly.
;~` ~ O ~ OSiEt3
\ / OH O
HO
CH3
EXA~PLE 20 ~[4-(3-hydroxy-5-oxo-l-cyclopenten-1-yl)-2Z-
butenyl]oxy]acetic acid
The title compound is prepared by the method of
Example 17 using l g of the title compound of Example 16.
~--~=/~ '--CO 2H
HO
XAMPLE 21 4-[(triethylsilyl)oxy]-2-[4-[2-oxo-3-
(triethylsilyl)oxy]propoxy]-2Z-butenyl]-2-cyclopenten-l-one
The title compound is prepared by the method of
Example 18 using 500 mg of the product from Example 20.
~29-
2~`
~ ~ OSiEt3
OSiEt3
EXAMPLE 22 4a-hydroxy-3~-(4-hydroxy-4-methyl-lE-
octenyl)-2a-[4 (3-hydroxy-2-oxopropoxy~-2Z-butenyl]
cyclopentanone
The title compound is prepared by the method of
Examples 4 and 6 using 500 mg of the product from
Example 21.
~ ` ~--==~'`O ~ OH
OH CH3
-3~-
94
CHART A
-
CHO
¦ l)RC-C-(CH2)nMgX II
2) deprotection
(CH2) ~ III
OH
1 H+
o
~\~ (CH2)~_
IV
OH
alumina
~y (CH2) ~5_
~ V
HO
` ¦ Protecting
~ .reagent
O
~ / (CH2)n`~~=~-- VI
RloO
-31-
2~
CHART B
Cu
~ oSi(alkyl)3 XI
\/~\R2
Rl
1) VI
~ ~2) (~lkyl)3SiX
(alkyl) 3sio
~ \ y ~ 2 n os~alkyl)3 XII
R O"" ~ R2
¦ 1) (CH2)n ~ Me2NCHO
2 ) R30CCH 2X
\ ~ O
(alkyl) 3sio
(CH2)n ~ ~ `COR3 XIII
OCi(al~1)3 O
~"` ~`~
-Rlo Rl R2
~ H-~
O
~ (CH2) = o XIV
H0 \~--~ R
Rl 2
catalytic
. h;ydrogenation
\ /
J~"` (CH2) n~~\o~ COR3
/ OH I l XV
~`\ ~\R
~ Rl 2
--32--
~2~ 9~
CHART C
XIII
catalytic
hydrogenation
(alkyl)3SiO
~CH2)n ~ ~ ~ COR3
psi (alkYl)3 0 XXI
Rlo ` Rl R2
~ H~
XV
-33-
CHART D
OSi (aikyl) 3
~ ( CH 2 ) n ~=~ ~O~~ COR3
Ro~ ( yl) 3 o XIII or XXI
1) LiAlH4
2) H+
t CH2 ) ~3~ `OH
OH XXXI
HO\~ R
n 2
L~l
--34--
9a~`
CHART E
III (n=l)
1) ~ H~
2) (CH20)n , base
\ 3) R30CCH2X
O ~ COR3 XLI
0 ~ 0
catalytic
. hydrogenation
. ~ ~ ~ \ O ~ COR3 XLII
0~ 0
g~
CHART Y
~ / ~ 0 ~'~ COR3 XLI or XLII
O ~ ~
+
2) Aqueous base
O ` /
~ O ~ CO2H LI
HO`
¦~lkyl)3SiX
'O
~ ~~~O'~~ COSi(alkyl)3 LII
(alkyl)3SiO~`
1) (COCl)2 , Me~NCHO
2) Me3SiOCH=C(OSiMe3)2
O 3) H+
O ~ ~ \ OH
~ O :LIII
HO`
1 (alkyl)3SiX
o
~ OSi(alkyl)3
~ O LIV
(alkyl) 3sio~ !
I 1) XI
1 2) H+
I!
~ ~ O ~ OH LV
HO~ ~ ~
1 2
-35-
