Note: Descriptions are shown in the official language in which they were submitted.
2 ~ 82 1 9 1
The invention relates to new leukotriene-B4 derivatives,
process for their production and their use as pharmaceutical
agents. The new compounds are optically active structuraI
analogues of previously known leukotriene-B4 antagonists, which
contain a six-membered ring as a basic structural element (DE-A
39 17 597, DE-A 42 27 790.6). Leukotriene B4 (LTB4)
was discovered by B. Samuelsson et al. as a metabolite of the
arachidonic acid. In the biosynthesis, leukotriene A4 is formed
by the enzyme 5-lipoxygenase first as a central intermediate
product, which then is converted by a specific hydrolase to the
LTB4.
2 21~2191
H, OOH
COOHLipoxY~enase ~ ~ ~ COOH
Arachidonsaure / 5-HPETE
~hydrase
COOH
~, C5H
Leukotrien A4 (LTA4)
\Hydrolase
Glut~thion- ~ H, ~ ~ ~ COOH
S-t~ansferase
SHll
~0 ~H Leuko~ien B4 (LTB4)
~ ~ _ ~ ~ ~ COOH
1~=~, CsHll Cys-Gly
~-GIu
Leuko~ien C4 (LTC4)
KEY:
Arachidonsaure = arachidonic acid
Leukotrien A4 (LTA4) = leukotriene A4 (LTA4)
Glutathion - S-transferase = glutathione - S-transferase
Leukotrien B4 (LTB4) = leukotriene B4 (LTB4)
Leukotrien C4 (LTC4) = leukotriene C4 (LTC4)
2 ~ 82 1 9 1
The nomenclature of the leukotrienes can be gathered from
the following works:
a) B. Samuelsson et al., Prostaglandins 19, 645 (1980); 17,
785 (1979).
b) C. N. Serhan et al., Prostaglandins 34, 201 (1987).
The physiological and especially the pathophysiological
importance of leukotriene B4 is summarized in several more recent
works: a) The Leukotrienes, Chemistry and Biology eds. L. W.
Chakrin, D. M. Bailey, Academic Press 1984. b) J. W. Gillard et
al., Drugs of the Future 12, 453 (1987). c) B. Samuelsson,
Sciences 237, 1171 (1987). d) C. W. Parker, Drug Development
Research 10, 277 (1987). It follows from the above that LTB4 is
an important inflammation mediator for inflammatory diseases, in
which leukocytes invade the affected tissue.
The effects of LTB4 are triggered on the cellular plane by
the bond of LTB4 on a specific receptor.
It is known concerning LTB4 that it causes the adhesion of
leukocytes on the blood vessel wall. LTB4 is chemotactically
effective, i.e., it triggers a directed migration of leukocytes
in the direction of a gradient of increasing concentration.
Furthermore, it indirectly changes the vascular permeability
based on its chemotactic activity, and a synergism with
prostaglandin E2 is observed. LTB4 obviously plays a decisive
role in inflammatory, allergic and immunological processes.
Leukotrienes and especially LTB4 are involved in skin
diseases, which are accompanied by inflammatory processes ~
(increased vascular permeability and formation of edemas, cell
2 1 ~32 i ~ 1
infiltration), increased proliferation of skin cells and itching,
such as, for example, in eczemas, erythemas, psoriasis, pruritus
and acne. Pathologically increased leukotriene concentrations
are involved either causally in the development of many
dermatitides or there is a connection between the persistence of
the dermatitides and the leukotrienes. Clearly increased
leukotriene concentrations were measured, for example, in the
skin of patients with psoriasis or atopic dermatitis.
Leukotrienes and especially LTB4 are also involved in the
diseases of internal organs, for which an acute or chronic
inflammatory component was described, e.g.: joint diseases
(arthritis); diseases of the respiratory tract (asthma, rhinitis
and allergies); inflammatory intestinal diseases (colitis); as
well as reperfusion damages (to the heart, intestinal or renal
tissues), which result by the temporary pathological obstruction
of blood vessels.
Further, leukotrienes and especially LTB4 are involved in
the disease of multiple sclerosis and in the clinical picture of
shock (triggered by infections, burns or in complications in
kidney dialysis or other separately discussed perfusion
techniques).
Leukotrienes and especially LTB4 further have an effect on
the formation of white blood cells in the bone marrow, on the
growth of unstriped muscle cells, of keratinocytes and of B-
lymphocytes. LTB4 is therefore involved in diseases with
inflammatory processes and in diseases with pathologically
increased formation and growth of cells.
21821 91
For example, leukemia or arteriosclerosis represent diseases
with this clinical picture.
By the antagonizing of the effects, especially by LTB4, the
active ingredients and their forms of administration of this
invention are specific medicines for diseases of humans and
animals, in which especially leukotrienes play a pathological
role.
Besides the therapeutic possibilities, which can be derived
from an antagonizing of LTB4 action with LTB4 analogues, the
usefulness and potential use of leukotriene-B4 agonists for the
treatment of fungus diseases of the skin were also able to be
shown (H. Katayama, Prostaglandins 34, 797 (1988)).
The invention relates to leukotriene-B4 derivatives of
general formula I
"`
(<~., ~
A ~ B-D-R3
OR2
in which
R1 represents CH20H, CH3, CF3, COOR4, CONR5R6, and
R2 represents H or an organic acid radical with 1-15 C
atoms,
R3 symbolizes H; C1-C14 alkyl, C3-C10 cycloalkyl optionally
substituted singly or multiply; C6-C10 aryl radicals,
independently of one another, optionally substituted
singly or multiply by halogen, phenyl, C1-C4 alkyl,
6 2182~91
C~-C4 alkoxyl, fluoromethyl, chloromethyl,
trifluoromethyl, carbo~yl, carboxyl or hydroxy; or a 5-
to 6-membered aromatic heterocyclic ring with at least
1 heteroatom,
R4 means hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl; C6-C10
aryl radicals optionally substituted by 1-3 halogen,
phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl,
chloromethyl, trifluoromethyl, carboxyl or hydroxy;
CH2-CO-(C6-C10) aryl or a 5- to 6-membered ring with at
least 1 heteroatom,
A symbolizes a trans, trans-CH=CH-CH=CH, a -CH2CH2-CH=CH-
or a tetramethylene group,
B symbolizes a C1-C10 straight-chain or branched-chain
alkylene group, which optionally can be substituted by
fluorine or the group
--C-- CH2-- or --CH2~C\
(CH2)n (CH2)n
D means a direct bond, oxygen, sulfur, -C-C-, -CH=CR7, or
together with B can also mean a direct bond,
Rs and R6 are the same or different, and represent H or C1-C4
alkyl optionally substituted by hydroxy groups or R6
represents H and Rs represents C1-C15 alkanoyl or R8SO2,
and optionally are substituted with OH,
R7 means H, C1-C5 alkyl, chlorine, bromine,
R8 has the same meaning as R3,
m means 1-3,
7 2182191
n is 2-5, and, if R4 means hydrogen, their salts with
physiologically compatible bases and their cyclodextrin
clathrates,
X and Y mean a direct bond, whereby the resulting olefin can
be E- or Z-configured or X represents a fluorine atom
in ~- or B-position, and Y means a hydrogen atom in B-
position.
The group OR2 can be in ~- or B-position. Formula I
comprises both racemates and the possible pure diastereomers and
enantiomers.
As alkyl groups R4, straight-chain or branched-chain alkyl
groups with 1-10 C atoms are considered, such as, for example,
methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl,
neopentyl, hexyl, heptyl, decyl.
Alkyl groups R4 can optionally be substituted singly to
multiply by halogen atoms, alkoxy groups, optionally substituted
aryl or aroyl groups with 6-10 C atoms (relative to possible
substituents, see under aryl R4), dialkylamino and
trialkylammonium with 1-4 C atoms in the alkyl portion, whereby
the single substitution is to be preferred. As substituents, for
example, fluorine, chlorine or bromine, phenyl, dimethylamino,
diethylamino, methoxy, ethoxy can be mentioned. As preferred
alkyl groups R4, those with 1-4 C atoms can be mentioned.
Cycloalkyl group R4 can contain 3-10, preferably 5 and 6
carbon atoms in the ring. The rings can be substituted by alkyl
groups with 1-4 carbon atoms. For example, cyclopentyl,
cyclohexyl, methylcyclohexyl can be mentioned.
8 2 1 82 1 9 1
As aryl groups R4, both substituted and unsubstituted aryl
groups with 6-10 C atoms are considered, such as, for example,
phenyl, 1-naphthyl and 2-naphthyl, which can be substituted in
each case by 1-3 halogen atoms (F, Cl, Br), a phenyl group, 1-3
alkyl groups with, in each case, 1-4 C atoms, a chloromethyl, a
fluoromethyl, trifluoromethyl, carboxyl, hydroxy or alkoxy group
with 1-4 C atoms. Preferred substituents in 3- and 4-position on
the phenyl ring are, for example, fluorine, chlorine, alkoxy or
trifluoromethyl, in 4-position, however, hydroxy.
As heterocyclic groups R4, 5- and 6-membered aromatic
heterocycles are suitable, which contain at least 1 heteroatom,
preferably nitrogen, oxygen or sulfur. For example, 2-furyl, 2-
thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl,
pyrimidinyl, pyridazinyl, 3-furyl, 3-thienyl, 2-tetrazolyl, i.a.,
can be mentioned.
As acid radical R5, such physiologically compatible acids
are suitable. Preferred acids are organic carboxylic acids and
sulfonic acids with 1-15 carbon atoms, which belong to the
aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic and
heterocyclic series. These acids can be saturated, unsaturated
and/or polybasic and/or substituted in the usual way. As
examples of the substituents, C14 alkyl, hydroxy, C14 alkoxy, oxo
or amino groups or halogen atoms (F, Cl, Br) can be mentioned.
For example, the following carboxylic acids can be mentioned:
formic acid, acetic acid, propionic acid, butyric acid,
isobutyric acid, valeric acid, isovaleric acid, caproic acid,
oenanthic acid, caprylic acid, pelargonic acid, capric acid,
9 2 1 82 1 ~ 1
undecylic acid, lauric acid, tridecylic acid, myristic acid,
pentadecylic acid, trimethylacetic acid, diethylacetic acid,
tert-butylacetic acid, cyclopropylacetic acid, cyclopentylacetic
acid, cyclohexylacetic acid, cyclopropanecarboxylic acid,
cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic
acid, methoxyacetic acid, ethoxyacetic acid, mono-, di- and
trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid,
piperidinoacetic acid, morpholinoacetic acid, lactic acid,
succinic acid, adipic acid, benzoic acid; benzoic acids
substituted with halogen (F, Cl, Br) or trifluoromethyl, hydroxy,
C14 alkoxy or carboxy groups; nicotinic acid, isonicotinic acid,
furan-2-carboxylic acid, cyclopentylpropionic acid. As preferred
arylsulfonyl radicals and alkanesulfonyl radicals R8SO2, those
are to be considered that are derived from a sulfonic acid with
up to 10 carbon atoms. As sulfonic acids, for example,
methanesulfonic acid, ethanesulfonic acid, isopropanesulfonic
acid, B-chloroethanesulfonic acid, butanesulfonic acid,
cyclopentanesulfonic acid, cyclohexanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid, p-
chlorobenzenesulfonic acid, N,N-dimethylaminosulfonic acid, N,N-
diethylaminosulfonic acid, N,N-bis-(B-chloroethyl)-aminosulfonic
acid, N,N-diisobutylaminosulfonic acid, N,N-dibutylaminosulfonic
acid, pyrrolidino, piperidino, piperazino, M-methylpiperazino and
morpholinosulfonic acid are suitable.
As alkyl groups R3, straight-chain and branched-chain,
saturated and unsaturated alkyl radicals, preferably saturated,
with 1-14, especially 1-10 C atoms, are suitable, which
2 1 82 ~ 9 ~
optionally can be substituted by optionally substituted phenyl
(for substitution, see under aryl Rs)~ For example, methyl,
ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl,
heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, benzyl,
m- and p-chlorobenzyl groups can be mentioned. If alkyl groups
R3 are halogen-substituted, fluorine, chlorine and bromine are
suitable as halogens.
As examples of halogen-substituted alkyl groups R3, alkyls
with terminal trifluoromethylene groups are considered.
Cycloalkyl group R3 can contain 3-10, preferably 3-6 carbon
atoms in the ring. The rings can be substituted by alkyl groups
with 1-4 carbon atoms optionally by halogens. For example,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl-
cyclohexyl, fluorocyclohexyl can be mentioned.
As substituted or unsubstituted aryl groups R3, for example,
phenyl, 1-naphthyl and 2-naphthyl, which can be substituted in
each case by 1-3 halogen atoms (F, Cl, Br), a phenyl group, 1-3
alkyl groups with 1-4 C atoms in each case, a chloromethyl,
fluoromethyl, trifluoromethyl, carboxyl, C~-C4 alkoxy or hydroxy
group, are considered. Preferred is the substitution in 3- and
4-position on the phenyl ring by, for example, fluorine,
chlorine, alkoxy or trifluoromethyl or in 4-position by hydroxy.
As heterocyclic aromatic groups R3, 5- and 6-membered
heterocycles that contain at least 1 heteroatom, preferably
nitrogen, oxygen or sulfur, are suitable. For example, 2-furyl,
2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl,
11 21 821 9 1
pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl, i.a.,
can be mentioned.
As alkylene group B, straight-chain or branched, saturated
or unsaturated alkylene radicals, preferably saturated with 1-10,
especially with 1-5 C atoms, are suitable, which optionally can
be substituted by fluorine atoms. For example, methylene,
fluoromethylene, difluoromethylene, ethylene, 1,2-propylene,
ethylethylene, trimethylene, tetramethylene, pentamethylene, 1,2-
difluoroethylene, l-fluoroethylene, l-methyltetramethylene, 1-
methyl-tri-methylene, 1-methylene-ethylene, l-methylene-
tetramethylene can be mentioned.
Alkylene group B can further represent the group
- C- CH2- or - CH2/C\-
(CH2)n (CH2)nwhereby n = 2-5, preferably 3-5.
As acid radicals R2, those of physiologically compatible
acid radicals are suitable. Preferred acids are organic
carboxylic acids and sulfonic acids with 1-15 carbon atoms, which
belong to the aliphatic, cycloaliphatic, aromatic, aromatic-
aliphatic or heterocyclic series. These acids can be substituted
saturated, unsaturated and/or polybasic and/or in the usual way.
As examples of the substituents, C14 alkyl, hydroxy, C~,4 alkoxy,
oxo or amino groups or halogen atoms (F, Cl, Br) can be
mentioned. For example, the following carboxylic acids can be
mentioned: formic acid, acetic acid, propionic acid, butyric
acid, isobutyric acid, valeric acid, isovaleric acid, caproic
acid, oenanthic acid, caprylic acid, pelargonic acid, capric
2182191
acid, undecylic acid, lauric acid, tridecylic acid, myristic
acid, pentadecylic acid, trimethylacetic acid, diethylacetic
acid, tert-butylacetic acid, cyclopentylacetic acid,
cyclohexylacetic acid, cyclohexanecarboxylic acid, phenylacetic
acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid,
mono-, di- and trichloroacetic acid, aminoacetic acid,
diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic
acid, lactic acid, succinic acid, adipic acid, benzoic acid;
benzoic acids substituted with halogen (F, Cl, Br) or
trifluoromethyl, hydroxy, C14 alkoxy or carboxy groups; nicotinic
acid, isonicotinic acid, furan-2-carboxylic acid,
cyclopentylpropionic acid. As preferred acid radicals R2 and R3,
those acyl radicals with up to lO carbon atoms are considered.
Alkyl radicals R5 and R6, which optionally contain hydroxy
groups, are straight-chain or branched alkyl radicals, especially
straight-chain, such as, for example, methyl, ethyl, propyl,
butyl, pentyl, hexyl, especially preferably methyl.
R7 as C15 alkyl means straight-chain or branched-chain alkyl
radicals as were already mentioned for R3 or R4. Preferred alkyl
radicals R7 are methyl, ethyl, propyl and isopropyl.
Inorganic and organic bases are suitable for salt formation,
as they are known to one skilled in the art for forming
physiologically compatible salts. For example, alkali
hydroxides, such as sodium hydroxide and potassium hydroxide,
alkaline-earth hydroxides, such as calcium hydroxide, ammonia,
amines, such as ethanolamine, diethanolamine, triethanolamine, N-
13 21 821 91
methylglucamine, morpholine, tris-(hydroxymethyl)-methylamine,
etc., can be mentioned.
To attain the cyclodextrin clathrates, the compounds of
formula I are reacted with ~-, B- or y-cyclodextrin. Preferred
are ~-cyclodextrin derivatives.
Preferred compounds of this invention are compounds of
general formula I, whereby the radicals have the following
meaning:
R1 is CH20H, CONR5R6, COOR4 with R4 meaning a hydrogen atom,
an alkyl radical with 1-10 C atoms, a cycloalkyl
radical with 5-6 C atoms, a phenyl radical optionally
substituted by 1-2 chlorine, bromine, phenyl, C14
alkyl, C14 alkoxy, chloromethyl, fluoromethyl,
trifluoromethyl, carboxy or hydroxy,
m is 1-3,
A is a trans-CH=CH-CH=CH or tetramethylene group;
B is a straight-chain or branched-chain, saturated or
unsaturated alkylene group with up to 10 C atoms, which
optionally can be substituted by fluorine, or the group
--C--CH2--
(CH2)n
with n = 2-5;
D is a direct bond, oxygen, sulfur, a -C--C group or a
-CH=CR7 group with R7 as hydrogen, C15 alkyl, chlorine
or bromine;
B and D are together a direct bond;
lg 2 1 82 1 9 1
R2 means hydrogen or an organic acid radical with l-lS C
atoms;
R5 and R6 have the above-indicated meanings;
R3 is a hydrogen atom, C110 alkyl, cycloalkyl with 5-6 C
atoms, a phenyl radical optionally substituted by 1-2
chlorine, bromine, phenyl, C1 4 alkyl, C14 alkoxy,
chloromethyl, fluoromethyl, trifluoromethyl, carboxy or
hydroxy, and if
R4 means a hydrogen, their salts with physiologically
compatible bases and cyclodextrin clathrates.
Especially preferred compounds of this invention are
compounds of general formula I, whereby the radicals have the
following meaning:
R1 is CH20H, CONR5R6, COOR4 with R4 meaning a hydrogen atom,
an alkyl radical with 1-4 C atoms,
R2 means hydrogen or an organic acid radical with 1-6 C
atoms,
R3 is a hydrogen atom or C110 alkyl;
R5 and R6 have the above-indicated meanings;
A is a trans, trans-CH=CH-CH=CH or tetramethylene group;
B is a straight-chain or branched-chain alkylene group
with up to 5 C atoms;
D is a direct bond or a -C-C group or a -CH=CR7 group
with R7 as hydrogen or C15 alkyl;
B and D are together a direct bond;
21 821 91
and if R4 means a hydrogen atom, their salts with
physiologically compatible bases and their cyclodextrin
clathrates.
In addition, the invention relates to a process for the
production of the compounds of general formula I according to the
invention, which is characterized in that an alcohol of formula
II or an intermediate sulfonic acid ester,
OH
A ~ B-D-R3
OR2
in which A, B, D, R1, R2 and R3 have the above-indicated meaning
and R'1 has the same meaning as R1 or represents grouping -CH20R9,
in which R9 means a readily cleavable ether radical, optionally
under protection of free hydroxy groups in OR2, is reacted with a
dehydrating reagent or fluorinating reagent of general formula
III,
F3SN(Alk)3 (III)
in which Alk represents -CH3 or -CH2CH3, optionally in the
presence of a base and optionally then separated in any sequence
of isomers, protected hydroxy groups are released and/or a free
hydroxy group is esterified and/or the 1-hydroxy group is
oxidized to carboxylic acid and/or double bonds are hydrogenated
and/or an esterified carboxyl group is saponified and/or reduced
or a carboxyl group is esterified and/or a free carboxyl group is
16 21 821 91
converted to an amide or a carboxyl group is converted to a salt
with a physiologically compatible base.
As ether radicals ~ in the compound of formula II, the
radicals that are familiar to one skilled in the art are
considered. Preferred are readily cleavable ether radicals, such
as, for example, dimethyl-tert-butylsilyl, trimethylsilyl,
tribenzylsilyl, diphenyl-tert-butylsilyl, tetrahydropyranyl,
tetrahydrofuranyl and ~-ethoxyethyl, to name only a few.
The reaction of the compound of general formula II with a
fluorinating reagent of general formula III is performed at
temperatures of -100C to 100C, preferably -78C to 80C in an
aprotic solvent or solvent mixture, for example, tetrahydrofuran,
diethyl ether, optionally in the presence of an amine. As
amines, for example, triethylamine, dimethylaminopyridine or
pyridine are suitable. In this reaction, in addition to the 5-
fluorine compound, the ~5~6-olefin, which can be separated by
chromatography, is also obtained.
If it is desired to obtain only the ~56-olefin, the hydroxy
group can be cleaved optionally with an intermediate sulfonic
acid ester. As a dehydrating reagent, for example, the so-called
Burgess reagent (J. Am. Chem. Soc. 90, 4744 (1968)) is suitable.
The reaction of the compound of general formula II to an
intermediate 9-sulfonic acid ester is carried out in a way known
in the art with an alkyl or aryl sulfonyl chloride or alkyl or
arylsulfonyl anhydride in the presence of an amine, such as, for
example, pyridine, triethylamine or DMAP at temperatures between
-60C and +100C, preferably -20C to +50C. The elimination of
17 21 821 91
the 5-sulfonate is carried out with a base, preferably potassium-
tert-butylate, 1,5-diazabicyclo[4.3.0]-non-5-ene or 1,8-
diazabicyclo~5.4.0]undec-7-ene in an inert solvent, such as, for
example, dimethylformamide, dimethylacetamide, dimethyl
sulfoxide, dimethoxyethane, tetrahydrofuran, etc., at
temperatures between 0C and 100C, preferably 20C to 80C.
The reduction to the compounds of formula I with R1 meaning
a CH20H group is performed with a reducing agent that is suitable
for the reduction of esters or carboxylic acids, such as, for
example, lithium aluminum hydride, diisobutyl aluminum hydride,
etc. As a solvent, diethyl ether, tetrahydrofuran,
dimethoxyethane, toluene, etc. are suitable. The reduction is
performed at temperatures of -30C up to boiling temperature of
the solvent used, preferably 0C to 30C.
The esterification of the alcohols of formula I (R2 = H) is
carried out in a way known in the art. For example, the
esterification is carried out in that an acid derivative,
preferably an acid halide or acid anhydride, is reacted with an
alcohol of formula I in the presence of a base such as, for
example, NaH, pyridine, triethylamine, tributylamine or 4-
dimethylaminopyridine. The reaction can be performed without a
solvent or in an inert solvent, preferably acetone, acetonitrile,
dimethylacetamide, dimethyl sulfoxide at temperatures above or
below room temperature, for example, between -80C to 100C,
preferably at room temperature.
The oxidation of the 1-hydroxy group is performed according
to methods that are known to one skilled in the art. As
18 2182l~l
oxidizing agents, for example, there can be used: pyridinium
dichromate (Tetrahedron Letters, 1979, 399), Jones reagent (J.
Chem. Soc. 1953, 2555) or platinum/oxygen (Adv. in Carbohydrate
Chem. 17, 169 (1962) or Collins oxidation (Tetrahedron Letters
1968, 3363 and subsequent Jones Oxidation. The oxidation with
pyridinium dichromate is performed at temperatures of 0C to
100C, preferably at 20C to 40C in a solvent that is inert with
respect to the oxidizing agent, for example, dimethylformamide.
The oxidation with Jones reagent is carried out at
temperatures of -40C to +40C, preferably 0C to 30C, in acetone
as a solvent.
The oxidation with platinum/oxygen is performed at
temperatures of 0C to 60C, preferably 20C to 40C, in a solvent
that is inert with respect to the oxidizing agent, such as, e.g.,
ethyl acetate.
The saponification of the esters of formula I is performed
according to the methods known to one skilled in the art, such
as, for example, with basic catalysts. The compounds of formula
I can be separated by the conventional separating methods into
optical isomers (Asymmetric Synthesis, Vol. 1-5, Ed. J. D.
Morrison, Academic Press, Inc., Orlando etc., 1985; Chiral
Separations by HPLC, Ed. A. M. Krstulovic; John Wiley & Sons; New
York etc. 1989).
The release of the functionally modified hydroxy groups is
carried out according to known methods. For example, the
cleavage of hydroxy protective groups, such as, for example, the
tetrahydropyranyl radical, is performed in an aqueous solution of
19 2 1 82 1 ~ 1
an organic acid, such as, e.g., oxalic acid, acetic acid,
propionic acid, i.a., or in an aqueous solution of an inorganic
acid, such as, e.g., hydrochloric acid. To improve the
solubility, a water-miscible inert organic solvent is suitably
added. Suitable organic solvents are, e.g., alcohols, such as
methol and ethanol, and ethers, such as dimethoxyethane, dioxane
and tetrahydrofuran. Tetrahydrofuran is preferably used. The
cleavage is performed preferably at temperatures between 20C and
80C. The cleavage of the silyl ether protective groups is
carried out, for example, with tetrabutylammonium fluoride or
with potassium fluoride in the presence of a crown ether (such
as, for example, dibenzo[18]-crown-6). As a solvent, for
example, tetrahydrofuran, diethyl ether, dioxane,
dichloromethane, etc., are suitable. The cleavage is performed
preferably at temperatures between 0C and 80C.
The saponification of the acyl groups is carried out, for
example, with alkali or alkaline-earth carbonates or -hydroxides
in an alcohol or in the aqueous solution of an alcohol. As an
alcohol, lower aliphatic alcohols, such as, e.g., methanol,
ethanol, butanol, etc., preferably methanol, are considered. As
alkali carbonates and -hydroxides, potassium and sodium salts can
be mentioned. Preferred are potassium salts.
As alkaline-earth carbonates and -hydroxides, for example,
calcium carbonate, calcium hydroxide and barium carbonate are
suitable. The reaction is carried out at -10C to +70C,
preferably at +25C.
21 821 ~1
The introduction of ester group -COOR4 for R1, in which R4
represents an alkyl group with 1-10 C atoms, is carried out
according to the methods known to one skilled in the art. The 1-
carboxy compounds are reacted, for example, with
diazohydrocarbons in a way known in the art. The esterification
with diazohydrocarbons is carried out, e.g., in that a solution
of the diazohydrocarbon in an inert solvent, preferably in
diethyl ether, is mixed with the 1-carboxy compound in the same
solvent or in another inert solvent, such as, e.g., methylene
chloride. After the reaction is completed in 1 to 30 minutes,
the solvent is removed, and the ester is purified in the usual
way. Diazoalkanes are either known or can be produced according
to known methods [Org. Reactions Vol. 8, pages 389-394 (1954)].
The introduction of ester group -COOR4 for R1, in which R4
represents a substituted or unsubstituted aryl group, is carried
out according to the methods known to one skilled in the art.
For example, the 1-carboxy compounds are reacted in an inert
solvent with the corresponding arylhydroxy compounds with
dicyclohexylcarbodiimide in the presence of a suitable base, for
example, pyridine, dimethylaminopyridine, triethylamine. As a
solvent, methylene chloride, ethylene chloride, chloroform, ethyl
acetate, tetrahydrofuran, preferably chloroform, are suitable.
The reaction is performed at temperatures between -30C and
+50C, preferably at 10C.
If C=C double bonds that are contained in the primary
product are to be reduced, the hydrogenation is carried out
according to methods known in the art.
21 21 821 91
The hydrogenation of the ~810-diene system is performed in a
way known in the art at low temperatures, preferably at about
-20C to +30C in a hydrogen atmosphere in the presence of a
noble metal catalyst. As a catalyst, for example, 10% palladium
on carbon is suitable.
The leukotriene-B4 derivatives of formula I with R4 meaning
a hydrogen can be converted to a salt with suitable amounts of
the corresponding inorganic bases with neutralization. For
example, in dissolving the corresponding acids in water, which
contains the stoichiometric amount of the base, the solid
inorganic salt is obtained after water is evaporated or after a
water-miscible solvent, e.g., alcohol or acetone, is added.
For the production of an amine salt, LTB4 acid is dissolved
in, e.g., a suitable solvent, for example, ethanol, acetone,
diethyl ether, acetonitrile or benzene, and at least the
stoichiometric amount of the amine is added to the solution. In
this way, the salt usually accumulates in solid form or is
isolated after the solvent is evaporated in the usual way.
The introduction of amide group -CONH~ with ~ meaning
alkanoyl is carried out according to the methods known to one
skilled in the art. The carboxylic acids of formula I (R4=H) are
first converted to the mixed anhydride in the presence of a
tertiary amine, such as, for example, triethylamine, with
chloroformic acid butyl ester. The reaction of the mixed
anhydride with the alkali salt of the corresponding amide or with
ammonia (Rs=H) is carried out in an inert solvent or solvent
mixture, such as, for example, tetrahydrofuran, dimethoxyethane,
22 2 1 82 1 9 1
dimethylformamide, hexamethylphosphoric acid triamide, at
temperatures between -30C and +60C, preferably at 0C to 30C.
Another type of production of the amides involves the amidolysis
of 1-ester (R1 = COOR4) with the corresponding amine.
Another possibility for the introduction of amide group
-CONHRs involves the reaction of a 1-carboxylic acid of formula I
(R4 = H), in which free hydroxy groups are optionally
intermediately protected, with compounds of formula IV,
O = C = N - Rs (IV)
in which R5 has the above-indicated meaning.
The reaction of the compound of formula I (R4=H) with an
isocyanate of formula IV is carried out optionally with the
addition of a tertiary amine, such as, e.g., triethylamine or
pyridine. The reaction can be performed without a solvent or in
an inert solvent, preferably acetonitrile, tetrahydrofuran,
acetone, dimethylacetamide, methylene chloride, diethyl ether,
toluene, at temperatures between -80C to 100C, preferably at 0C
to 30C.
For the production of the other amides, for example, the
desired acid anhydride can be reacted with ammonia or the
corresponding amines.
If the starting product contains OH groups in the
leukotriene-B4 radical, these OH groups are also brought to
reaction. If end products that contain free hydroxyl groups are
ultimately desired, a start is suitably made from startlng
products in which the latter are intermediately protected by
preferably readily cleavable ether or acyl radicals.
23 2 1 ~2 i 9 1
The separation of the diastereomers is carried out according
to methods known to one skilled in the art, for example by column
chromatography.
The compounds of formula II that are used as starting
material are described in DE-A 42 27 790.6 or can be produced,
for example, by cis-1,2-diacetoxymethyl-cyclohex-4-ene or cis-
1,2-diacetoxymethyl-cyclohexane or cis-1,2-diacetoxymethyl
cyclopentane or cis-1,2-diacetoxymethylcycloheptane being
enantioselectively hydrolyzed with a lipase in a way known in the
art (J. B. Jones et al., J. Chem. Soc. Chem. Commun. 1985, 1563;
M. Schneider et al., Tetrahedron Lett. 26, 2073 (1985); H. J.
Gais et al., Tetrahedron Lett. 28, 3471 (1987)). The optically
active monoacetate that is produced in this way is then converted
to the tert-butyldimethylsilyl ether, optionally hydrogenated and
then converted with diisobutyl aluminum hydride to the monosilyl
ether of formula V
Rl2
CH20H
in which R1ol R11 and R12 are the same or different and mean Cl-C4
alkyl or phenyl.
By the oxidation, e.g., with Collins reagent or by the Swern
process (Tetrahedron Letters 34, 1651 (1978)), the aldehyde of
24 2182191
formula VI is obtained
Rl2
~CHO CVI)
(EtO)2PCH2CO2Et ~I) oder
O or
~tO)2P-CH2CH=CH-COOEt (Vl~)
which is converted in a Wittig-Horner olefination with the
phosphonate of formula VII and a base and optionally subsequent
hydrogenation as well as subsequent reduction of the ester group,
oxidation of the primary alcohol, repeated Wittig-Horner
olefination with the phosphonate of formula VII and optionally
subsequent hydrogenation to the ester of formula IX or a Wittig-
Horner reaction of the aldehyde of formula VI with a phosphonate
of formula VIII, whereby A
OSI-Rlo
A- COOEt
has the above-indicated meaning. As bases, for example,
potassium tert-butylate, diazabicyclononane, diazabicycloundecane
21 821 91
or sodium hydride are suitable. Reduction of the ester group,
for example with diisobutyl aluminum hydride, and subsequent
oxidation of the primary alcohol obtained, e.g., with manganese
dioxide or Collins reagent, results in an aldehyde of formula X
Rl2
Si-RIo (X)
A - CHO
The organometallic reaction of the aldehyde of formula X
with a Grignard reagent of formula XI, in which B, D
X-Mg-B-D-R3 (XI)
and R3 have the above-indicated meanings and X means chlorine,
bromine or iodine, results, under protection of the hydroxy
groups (for example by acylation) and optionally diastereomer
separation, in the compounds of formula XII
~' OSi- Rlo X~
A ~ B-D-R3
OR2
The production of the compound of formula XI that is
required for the organometallic reaction is carried out by
reaction of the corresponding terminal halide with magnesium. By
reaction of silyl ether XII with tetrabutylammonium fluoride and
26 2182191
optionally diastereomer separation, the alcohol of formula XIII
is obtained.
`" OH
OR2
The compounds of formula XII, in which B means a CHz group
and D means a -C-C group or a CH=CR7 group, can be obtained, for
example, by an organometallic reaction of a propargyl halide and
subsequent alkylation with a corresponding alkyl halide and
optionally subsequent Lindlar hydrogenation.
An alternative structure of the lower chain starts from the
aldehyde of formula XIV, which resulted from the Wittig-Horner
reaction of aldehyde VI and subsequent reduction and oxidation.
Rl2
~ ~ CHO
Wittig-Horner olefination of aldehyde XIII with a
phosphonate of formula XV
O O
(cH3o)2pcHrc-B-D-R3 (XY)~
- 27 2182191
and reduction of the ketone that is produced then resulted in an
alcohol of formula XII and, after acylation and silyl ether
cleavage, in an alcohol of formula III, which optionally can be
separated into diastereomers.
The compounds of general formula XIII are described in DE-A
42 27 790.6 or can be produced according to the process that is
presented in DE-A 42 27 790.6.
The oxidation of the primary alcohol group in XIII, e.g.,
with Collins reagent or pyridinium dichromate or with the Swern
method results in an aldehyde of formula XVI
"~ CHO
A ~ B-D-R3
OR2
The reaction of the aldehyde of general formula XVI with a
magnesium-organic compound of formula
HalMg-CH2~CH2~cH2~R 1 (XVII)
in which Hal represents chlorine, bromine or iodine, and R'
represents -CH3, CF3 or -CH20R9, in which R9 means a readily
cleavable ether radical, results in an alcohol of general formula
II. Then, isomers can be separated optionally in any sequence,
protected hydroxy groups can be released and/or a free hydroxy
group oxidized to carboxylic acid and/or double bonds
hydrogenated and/or an esterified carboxyl group (R1 = COORs)
saponified and/or a carboxyl group (~ = H) esterified and/or a
28 21 82lql
free carboxyl group (~ = H) converted to an amide (R~ = CONR6R7)
or a carboxyl group converted to a salt with a physiologically
compatible base.
As ether radicals ~ in the compound of formula II, the
radicals that are familiar to one skilled in the art are
considered. Preferred are readily cleavable ether radicals, such
as, for example, dimethyl-tert-butylsilyl, trimethylsilyl,
tribenzylsilyl, diphenyl-tert-butylsilyl, tetrahydropyranyl,
tetrahydrofuranyl and ~-ethoxyethyl, to name only a few.
The reaction of the compound of formula II with an
organometallic compound of formula XVII is carried out in a way
known in the art in an inert solvent or solvent mixture, such as,
for example, dioxane, toluene, dimethoxyethane or preferably
diethyl ether or tetrahydrofuran. The reaction is performed at
temperatures between -100C and 60C, preferably at 78C to 0C.
The production of compound XVII that is required for this
reaction is carried out by reaction of the corresponding hydroxy
halide that is protected by a readily cleavable ether group and
subsequent reaction with magnesium.
The incorporation of the chemically and metabolically labile
cis-~6~7 double bond of LTB4 into a cis-1,2-substituted cycloalkyl
ring results in a stabilization, whereby especially by further
derivatization of the functional groups and/or structural changes
of the lower side chain, LTB4 derivatives that can act as LTB4
antagonists were obtained (DE-A 39 17 597 and DE-A 42 27 790.6
and DE-A 41 08 351 and 41 39 886.8).
2 ~ ~2 1 9 1
It has now been found that by substitution of the 5-hydroxy
group by a fluorine atom or by introduction of a double bond in
5,6-position (numbering system beginning with a carboxy-C atom
with 1) and omission of the hydroxy group in 5-position in such
leukotriene-B4 derivatives, a prolonged duration of action,
greater selectivity and better effectiveness can be achieved.
The compounds of formula I act in an antiinflammatory,
antiallergic and antiproliferative manner. In addition, they
have antimycotic properties. Consequently, the new leukotriene-
B4 derivatives of formula I represent valuable pharmaceutical
active ingredients. The compounds of formula I are especially
suitable for topical administration, since they exhibit a
dissociation between desired topical effectiveness and
undesirable systemic side effects.
The new leukotriene-B4 derivatives of formula I are suitable
in combination with the additives and vehicles that are commonly
used in galenic pharmaceutics for topical treatment of diseases
of the skin, in which leukotrienes play an important role, e.g.:
contact dermatitis, eczemas of the most varied types,
neurodermatoses, erythrodermia, pruritus vulvae et ani, rosacea,
cutaneus lupus erythematosus, psoriasis, lichen ruber planus et
verrucosis and similar skin diseases.
In addition, the new leukotriene-B4 antagonists are suitable
for the treatment of multiple sclerosis and symptoms of shock.
The production of the pharmaceutical agent specialties is
carried out in the usual way by the active ingredients being
converted with suitable additives to the desired form of
2l 8 2l ql
administration, such as, for example: solutions, ointments,
creams or patches.
In the thus formulated pharmaceutical agents, the active
ingredient concentration depends on the form of administration.
In lotions and ointments, an active ingredient concentration of
0.0001% to 3% is preferably used.
Further, the new compounds optionally in combination with
the usual vehicles and adjuvants are also well-suited for the
production of inhalants, which can be used to treat allergic
diseases of the respiratory system, such as, for example,
bronchial asthma or rhinitis.
Further, the new leukotriene-B4 derivatives are also
suitable in the form of capsules, tablets or coated tablets,
which preferably contain 0.1 to 100 mg of active ingredient and
are administered orally or in the form of suspensions, which
preferably contain 1-200 mg of active ingredient per dosage unit,
and are also administered rectally to treat diseases of the
internal organs, in which leukotrienes play an important role,
such as, e.g.: allergic diseases of the intestinal tract, such
as colitis ulcerosa and colitis granulomatosa.
In these new forms of administration, the new LTB4
derivatives, in addition to the treatment of diseases of internal
organs with inflammatory processes, are also suitable for the
treatment of diseases in which, leukotriene-dependent, the
increased growth and the new formation of cells are important.
Examples are leukemia (increased growth of white blood cells) or
31 2l82l9l
arteriosclerosis (increased growth of unstriped muscle cells of
blood vessels).
The new leukotriene-B4 derivatives can also be used in
combination, such as, e.g., with lipoxygenase inhibitors,
cyclooxygenase inhibitors, glucocorticoids, prostacyclin
agonists, thromboxane antagonists, leukotriene-D4 antagonists,
leukotriene-E4 antagonists, leukotriene-F4 antagonists,
phosphodiesterase inhibitors, calcium antagonists, PAF
antagonists or other known forms of treatment of the respective
dlseases.
The following embodiments are used for a more detailed
explanation of the process according to the invention. In the
examples, diastereomers in 12-position that are not characterized
in more detail were characterized as polar or nonpolar (e.g.,
diastereomer unpol (12)).
32 2~2191
Example 1
5-r(E)-(2S)-2-~(lE,3E~-(5S)-5-Hydroxy-6,6-trimethYlene-9-phenyl-
1,3-nonadien-8-inyl)-cyclohexylidene~-pentanoic acid
diastereomer Pol (12)
0.39 ml of diethylamino sulfur trifluoride is added in drops
to a solution of 1.82 g of (5S)-5-hydroxy-5-[cis-(2S)-2-((lE,3E)-
(5S)-5-acetoxy-6,6-trimethylene-9-phenyl-1,3-nonadien-8-inyl)-
(lS)-cyclohexyl]-pentan-l-ol-tert-butyldimethylsilyl ether
(diastereomer pol (12)) in 28 ml of dichloromethane and 0.78 ml
of pyridine at -70C under argon, and it is stirred for 2 hours
at -70C. It is allowed to heat to room temperature, a 5~ sodium
bicarbonate solution is carefully added, stirred for 15 minutes,
diluted with 200 ml of dichloromethane and washed with 30 ml of
brine each. It is dried on sodium sulfate and concentrated by
evaporation in a vacuum. The residue is separated by
chromatography on silica gel. With hexane/ethyl acetate (97+3
and 94+6), first obtained as a nonpolar component is 280 mg of 5-
[(E)-(2S)-2-((lE,3E)-(5S)-5-acetoxy-6,6-trimethylene-9-phenyl-
1,3-nonadien-8-inyl-cyclohexylidene]-pentan-1-ol-tert-
butyldimethylsilyl ether, 800 mg of mixed fractions, and obtained
as a polar component is 550 mg of (5R)-5-fluoro-5-[cis-(2S)-2-
((lE,3E)-(5S)-5-acetoxy-6,6-trimethylene-9-phenyl-1,3-nonadien-8-
inyl-(lS)-cyclohexyl]-pentan-l-ol-tert-butyldimethylsilyl ether
as a colorless oil.
IR spectrum of the olefin: (CHCl3) 2930, 2858, 1729, 1248,
990, 837 cm~1.
33 2 1 82 1 9 1
For silyl ether cleavage, 220 mg of the nonpolar olefin,
produced above, in 12 ml of tetrahydrofuran is stirred with 363
mg of tetrabutylammonium fluoride for 3 hours at 24C under
argon. Then, it is diluted with diethyl ether, washed three
times with water, dried on sodium sulfate and concentrated by
evaporation in a vacuum. The residue is chromatographed with
hexane/ethyl acetate (8+2) on silica gel. In this case, 140 mg
of l-alcohol is obtained as a colorless oil (polar component).
As a nonpolar component, 50 mg of the Z-configured ~5~6-olefin is
separated here.
IR: 3430, 2925, 2850, 2220, 1735, 1665, 1240, 992 cm~1.
For oxidation of the 1-hydroxy group, 1.6 g of Collins
reagent (bis-pyridine-chromium(VI) oxide complex; Tetrahedron
Letters 1968, 3363) is added at 0C to 350 mg of the alcohol,
produced above, in 25 ml of dichloromethane, and it is stirred
for lO minutes at 0C. Then, it is diluted with a mixture of
hexane/diethyl ether (1+1), Celite is added, filtered, washed
with hexane/diethyl ether (1+1) and concentrated by evaporation
in a vacuum. The thus obtained 1-aldehyde is used immediately
without further purification.
0.52 ml of Jones reagent (chromium(VI) oxide in H2SO4; J.
Chem. Soc. 1953, 2555) is added in drops to a solution of 320 mg
of the aldehyde, produced above, in 6 ml of acetone while being
stirred at -20C, and it is stirred for 10 minutes at -20C under
argon. Then, 2.5 ml of isopropanol is added, it is stirred for 5
34 21 1:321 91
minutes, diluted with 50 ml of diethyl ether, shaken twice with
brine, dried on sodium sulfate and concentrated by evaporation in
a vacuum. The residue is chromatographed on silica gel. With
hexane/ethyl acetate (3+2), 260 mg of the 1-carboxylic acid is
obtained as a colorless oil.
IR: 3520, 2935, 2860, 1728, 1245, 992 cm~1.
For acetate saponification, 5.3 ml of a 0.5N sodium
hydroxide solution is added to 250 mg of the acid, produced
above, in 5 ml of methanol at 25C, and it is stirred for 5 hours
at 25C under argon. Then, it is acidified with lN sulfuric acid
to pH 4-5. It is extracted with ethyl acetate, washed twice with
brine, dried on sodium sulfate and concentrated by evaporation in
a vacuum. The residue is chromatographed on silica gel. With
ethyl acetate, 211 mg of the title compound is obtained as a
colorless oil.
IR: 3400, 2930, 2855, 2220, 1708, 1599, 1490, 992 cm~~.
The starting material for the above compound is produced as
follows:
la~ 2-Oxo-3,3-trimethylene-6-Phenyl-hex-5-ine-phosphonic acid
dimethyl ester
250 ml of a 1.6 molar butyllithium solution in hexane and
then a solution of 20 g of cyclobutanecarboxylic acid in 20 ml of
tetrahydrofuran are added to a solution of 4.1 g of
diisopropylamine in 180 ml of tetrahydrofuran at -30C. It is
stirred for another 40 minutes at -10C, and then 43 g of 1-
21 ~21 ql
bromo-3-phenyl-2-propine is added in drops, stirred for 16 hours
at 25C and poured onto 400 ml of ice water. After acidification
with 2N hydrochloric acid to pH 4, it is extracted with diethyl
ether, the extract is washed with brine, dried on magnesium
sulfate and concentrated by evaporation in a vacuum. The residue
is dissolved in 83 ml of methanol, mixed with 4.3 ml of
concentrated sulfuric acid and refluxed for 6 hours. It is
cooled, ice water is stirred in and extracted with diethyl ether.
The extract is washed neutral with water, dried with sodium
sulfate, and the diethyl ether is concentrated by evaporation in
a vacuum. After distillation (boiling point 123-125C at 0.05
mm), 43 g of 2,2-trimethylene-5-phenyl-pent-4-inoic acid methyl
ester is obtained.
268 ml of 1.6 M butyllithium solution in hexane is added in
drops to a solution of 59 g of methanephosphonic acid dimethyl
ester in 700 ml of tetrahydrofuran at -70C. After 1 hour, a
solution of 44 g of the ester, produced above, in 120 ml of
tetrahydrofuran is added in drops and stirred for another 5 hours
at -70C. Then, it is mixed with 35 ml of ethyl acetate and
concentrated by evaporation in a vacuum. The residue is
dissolved in 100 ml of water and extracted three times with 400
ml of dichloromethane each. It is dried on sodium sulfate and
concentrated by evaporation in a vacuum. The residue is purified
by column chromatography on silica gel. With ethyl acetate, 43 g
of the phosphonate is obtained as a colorless liquid.
IR: 3420, 2998, 2875, 1703, 1250 cm~1.
36 2182191
lb) cis-(lS)-1-(Tert-butyl-dimethYlsilyloxy-methyl)-2(R)-2-
formyl-cyclohexane
481 g of imidazole and 532 g of tert-butyldimethylsilyl
chloride are added to a solution of 500 g of cis-(lS)-
hydroxymethyl-(2R)-acetoxymethyl-cyclohex-4-ene (produced, for
example, according to K. Laumen et al., Tetrahedron Letters 26,
2073 (1985)) in 2400 ml of dimethylformamide at 0C, and it is
stirred for 20 hours at 24C. It is diluted with diethyl ether,
shaken with 500 ml of a 5% sulfuric acid, washed neutral with
brine, dried on magnesium sulfate and concentrated by evaporation
in a vacuum. The residue is chromatographed on silica gel. With
hexane/ethyl acetate mixtures, 519 g of cis-(lS)-tert-butyl-
dimethylsilyloxymethyl-(2R)-acetoxymethyl-cyclohex-4-ene is
obtained.
For hydrogenation, 379 g of the silyl ether, produced above,
in 2400 ml of ethyl acetate is stirred with 20 g of palladium-10%
on carbon under a hydrogen atmosphere at room temperature and
normal pressure. After 6 hours, no hydrogen absorption could be
detected. The reaction mixture was filtered and concentrated by
evaporation in a vacuum. In this case, 359 g of the hydrogenated
compound was obtained.
[~]D = -7 .1 (C = 1. 005, acetone)
For acetate cleavage, 194 ml of an approximately 1.2 molar
solution of diisobutyl aluminum hydride in toluene is added in
drops to a solution of 35 g of the silyl ether, produced above,
37 2 1 82 1 9 1
in 450 ml of toluene, and it is stirred for 15 minutes at -70C.
Subsequently, 80 ml of isopropanol and then 97 ml of water are
added in drops, stirred for 2 hours at 22C, filtered, washed
with toluene and concentrated by evaporation in a vacuum. The
residue is purified by chromatography on silica gel. With
hexane/ethyl acetate (9+1), 22 g of the alcohol is obtained as a
colorless oil.
[~]D = +3-5 (c = 1.350/acetone)
IR: 3420, 2925, 2858, 1465, 1255, 833 cm~1.
For conversion of the hydroxy group to the formyl group,
15.9 g of dimethyl sulfoxide in 60 ml of dichloromethane is added
in drops at -70C to a solution of 12 g of oxalyl chloride in 90
ml of dichloromethane, and it is stirred for 10 minutes at -60C.
A solution of 19.5 g of the alcohol, produced above, in 60 ml of
dichloromethane is added to this solution at -60C, it is stirred
for 1.5 hours at -60C, 30 ml of triethylamine is added in drops
and stirred for 1.5 hours at -50C. Then, it is poured into 100
ml of ice water, extracted twice with 50 ml of dichloromethane
each, washed with water, shaken once with 50 ml of 5% citric acid
and washed twice with brine. It is dried on sodium sulfate and
concentrated~by evaporation in a vacuum. 19.2 g of the aldehyde,
which is used without further purification, is obtained.
IR: 2930, 2858, 2730, 1713, 840 cm~1.
38 21821 91
-
lc) 3-~cis-(lS)-1-Tert-butyl-dimethylsilYloxymethyl)-(2S)-
cyclohex-2-yl~-(2E)-propen-1-al
20.7 ml of phosphonoacetic acid triethyl ester and then 13.9
ml of diazabicycloundecene (DBU) are added in drops to a
suspension of 4.42 g of lithium chloride in 300 ml of
acetonitrile under argon at room temperature, and it is stirred
for 15 minutes. Then, a solution of 19.12 g of the aldehyde,
produced under lb, in 40 ml of acetonitrile is added in drops,
stirred for 3 hours at 24C and then diluted with diethyl ether.
It is shaken in succession with water, 10% sulfuric acid and
water, dried with sodium sulfate and concentrated by evaporation
in a vacuum. The residue is chromatographed with hexane/diethyl
ether (9+1) on silica gel. In this case, 17 g of the ~,B-
unsaturated ester is obtained as a colorless oil.
IR: 2930, 2838, 1706, 1648, 1270, 840 cm~1.
To reduce the ester group, 86 ml of a 1.2 molar solution of
diisobutyl aluminum hydride in toluene is added in drops to a
solution of 17 g of the ester, produced above, in 240 ml of
toluene at -70C, and it is stirred for 30 minutes at -70C.
Subsequently, 30 ml of isopropanol and then 40 ml of water are
added in drops, stirred for 2 hours at 22C, filtered, washed
with dichloromethane and concentrated by evaporation in a vacuum.
The residue is chromatographed with hexane/ethyl acetate (4+1) on
silica gel. In this case, 14.5 g of the ally alcohol is obtained
as a colorless oil.
IR: 3610, 3450, 2930, 2858, 1460, 838 cm~1.
39 2182191
A solution of 14.4 g of the alcohol, produced above, in 280
ml of toluene is mixed with 44 g of manganese dioxide, and it is
stirred for 5 hours at 24C. Then, it is filtered, concentrated
by evaporation and chromatographed on silica gel. With
hexane/diethyl ether (9+1), 13.3 g of the aldehyde is eluted as a
colorless oil.
IR: 2930, 2860, 2740, 1685, 1630, 840 cm~1.
ld) (SS~-S-Acetoxy-l-[cis-(lS)-l-hydroxymethyl)-(2S)-cyclohex-2-
yl~-6,6-trimethylene-9-phenyl-(lE,3E)-1,3-nonadien-8-ine
A solution of 40.10 g of 2-oxo-3,3-trimethylene-6-phenyl-
hex-5-ine-phosphonic acid dimethyl ester in 290 ml of
dimethoxyethane is added in drops to a suspension of 5 g of
sodium hydride (60~ suspension in oil) in 190 ml of
dimethoxyethane at oCt and it is stirred for 1 hour at 0C.
Then, a solution of the aldehyde (30.75 g), described under lc),
in 350 ml of dimethoxyethane is added in drops, stirred for 1
hour at 0C, 4 hours at 25C and then poured onto 200 ml of
saturated ammonium chloride soluti~n. It is extracted three
times with diethyl ether, the organic phase is washed with water,
dried on magnesium sulfate and concentrated by evaporation in a
vacuum. The residue is purified by column chromatography on
silica gel. With hexane/diethyl ether (9+1), 41 g of the ~,B-
unsaturated ketone is obtained as a colorless oil.
IR: 2925, 2858, 1673, 1625, 1590, 1001, 838 cm~1.
21 ~21 91
To reduce the keto group, 4.75 g of Ce(III) chloride
heptahydrate is added to a solution of 40.5 g of the ketone,
described above, in 700 ml of methanol and 74 ml of
tetrahydrofuran at -60C, it is stirred for 20 minutes and then
mixed in portions with 5 g of sodium borohydride. It is stirred
for 20 minutes at -60C, mixed with 34 ml of acetone, stirred for
15 minutes, neutralized at room temperature with glacial acetic
acid and concentrated by evaporation in a vacuum. Then, the
residue is taken up in a diethyl ether/water mixture, the aqueous
phase is shaken with diethyl ether, the organic phase is washed
neutral with water, dried on sodium sulfate and concentrated by
evaporation in a vacuum. The residue is chromatographed several
times on silica gel columns. With hexane/ethyl acetate (8+2),
first 11 g of the nonpolar R-configured alcohol (5R)-5-hydroxy-1-
[cis-(lS)-l-(tert-butyl-dimethylsilyloxymethyl)-(2S)-cyclohex-2-
yl]-6,6-trimethylene-9-phenyl-(lE,3E)-1,3-nonadien-8-ine as well
as 18 g of the polar S-configured alcohol (5S)-5-hydroxy-l-[cis-
(lS)-1-tert-butyldimethylsilyloxymethyl)-(2S)-cyclohex-2-yl]-6,6-
trimethylene-9-phenyl-(lE,3E)-1,3-nonadien-8-ine are obtained as
colorless oils.
IR (polar alcohol): 3530, 2925, 2853, 990, 838 cm~1.
For acetylation, 30 ml of acetic anhydride is added to a
solution of 17.8 g of the polar alcohol, produced above, in 60 ml
of pyridine, and it is stirred for 16 hours at room temperature.
Then, it is concentrated by evaporation in a vacuum with the
addition of toluene, and the residue is chromatographed on silica
41 21821~
gel. With hexane/diethyl ether (9+1), 19.1 g of the acetate is
obtained as a colorless oil.
IR: 2925, 2852, 1727, 1245, 990, 838 cm1.
For silyl ether cleavage, 25 g of tetrabutylammonium
fluoride is added to 19.1 g of the acetate, produced above, in
480 ml of tetrahydrofuran at 0C, and it is stirred for 3 hours
at 24C. Then, it is diluted with diethyl ether and washed three
times with brine. It is dried on magnesium sulfate, concentrated
by evaporation in a vacuum, and the residue is chromatographed on
silica gel. With hexane/ethyl acetate (7+3), 14 g of the alcohol
is eluted as a colorless oil.
IR: 3450, 2930, 2858, 1729, 1245, 990 cml.
le) (5S)-5-HydroxY-5-rcis-l2S)-2-((lE,3E)-(5S)-5-acetoxy-6,6-
trimethylene-s-phenyl-l~3-nonadien-8-inyl)-(ls)-cyclohexyl~-
pentan-1-ol-tert-butyldimethylsilyl ether diastereomer pol (12)
45 g of Collins reagent (chromic acid-pyridine complex) is
added to a solution of 8.95 g of the alcohol, produced above
under ld), in 230 ml of dichloromethane at 0C, and it is stirred
for 15 minutes at 0C. Then, it is diluted with a mixture of
hexane/diethyl ether (2+1), Celite is added, filtered and
concentrated by evaporation in a vacuum. The thus obtained
aldehyde was used without further purification (raw yield 8.2 g).
IR: 2930, 2858, 2720, 1723, 1245, 990, 968 cm~1.
42 2l82lql
For Grignard reaction, a solution of 26.7 g of 4-chloro-1-
(tert-butyldimethylsilyloxy)-butane in 24 ml of tetrahydrofuran
is added in drops to 5.76 g of magnesium at 25C under argon, a
crystal of iodine was added and stirred for 30 minutes at 60C.
Then, it is diluted with 74 ml of tetrahydrofuran.
The solution of 4.6 g of the aldehyde, produced above, in 35
ml of tetrahydrofuran is added in drops to 23 ml of this Grignard
solution under argon at -70C, and it is stirred for 30 minutes
at -70C. It is mixed with saturated ammonium chloride solution,
extracted three times with diethyl ether, the organic phase is
shaken with brine, dried on sodium sulfate and concentrated by
evaporation in a vacuum. The residue is chromatographed on
silica gel. With hexane/diethyl ether (9+1), first obtained is
720 mg of the 5R-configured diastereomer alcohol and obtained as
polar component is 3.6 g of the 5-configured diastereomer alcohol
(title compound).
IR: 3580, 2923, 2850, 1728, 1245, 990, 965, 835 cm~1.
Example 2
(5R)-5-Fluoro-5-[cis-(2S)-2-((lE 3E)-(5S)-5-hYdroxy-6 6-
trimethylene-9-phenyl-1 3-nonadien-8-inyl)-(lS)-cyclohexyl~-
pentanoic acid diastereomer pol (12)
860 mg of tetrabutylammonium fluoride is added to a solution
of 540 mg of (5R)-5-fluoro-5-[cis-(2S)-2-((lE,3E)-(5S)-5-acetoxy-
6,6-trimethylene-9-phenyl-1,3-nonadien-8-inyl)-(lS)-cyclohexyl]-
pentan-l-ol-tert-butyldimethylsilyl ether in 24 ml of
tetrahydrofuran, produced in Example 1, and it is stirred for 3
43 2l8 2l 9l
hours at 24C under argon. Then, it is diluted with diethyl
ether, washed three times with water, dried on sodium sulfate and
concentrated by evaporation in a vacuum. The residue is
chromatographed with hexane/ethyl acetate (7+3) on silica gel.
In this case, 393 mg of 1-alcohol is obtained as a colorless
oil.
IR: 3450, 2930, 2860, 1738, 1243, 992 cm~1.
For oxidation of the 1-hydroxy group, 2.5 g of Collins
reagent is added at 0C to 580 mg of the alcohol, produced above,
in 30 ml of dichloromethane, and it is stirred for 10 minutes at
0C. Then, it is diluted with a mixture of hexane/diethyl ether
(1+1), Celite is added, filtered, washed with hexane/diethyl
ether (1+1) and concentrated by evaporation in a vacuum. The
thus obtained 1-aldehyde is used immediately without further
purification.
0.87 ml of Jones reagent is added in drops to a solution of
555 mg of the aldehyde, produced above, in 10 ml of acetone while
being stirred at -20C, and it is stirred for 15 minutes at -20C
under argon. Then, 3.8 ml of isopropanol is added, it is stirred
for 5 minutes, diluted with 50 ml of diethyl ether, shaken twice
with brine, dried on sodium sulfate and concentrated by
evaporation in a vacuum. The residue is chromatographed on
silica gel. With hexane/ethyl acetate (4+1), 520 mg of 1-
carboxylic acid is obtained as a colorless oil.
IR: 3450, 2930, 2860, 1738, 1708, 1238, 992 cm~1.
44 21~2191
For acetate saponification, 10 ml of a 0.5N sodium hydroxide
solution is added to 500 mg of the acid, produced above, in 10 ml
of methanol at 25C, and it is stirred for 5 hours at 25C under
argon. Then, it is acidified with lN sulfuric acid to pH 4-5.
It is extracted with ethyl acetate, washed twice with brine,
dried on sodium sulfate and concentrated by evaporation in a
vacuum. The residue is chromatographed on silica gel. With
ethyl acetate/hexane (4+1), 420 mg of the title compound is
obtained as a colorless oil.
IR: 3420, 2934, 2862, 2220, 1710, 1599, 993 cm1.
Example 3
5~ r (E)-(2S)-2-((lE,3E~-(SR)-5-Hydroxy-6,6-trimethylene-9-phenyl-
1,3-nonadien-8-inyl)-cyclohexYlidene~-pentanoic acid
diastereomer unpol ~12)
Analogously to Example 1, the title compound is obtained as
a colorless oil from the nonpolar R-configured alcohol (5R)-5-
hydroxy-1-[cis-(lS)-1-(tert-butyldimethylsilyloxymethyl)-(2S)-
cyclohex-2-yl]-6,6-trimethylene-9-phenyl-(lE,3E)-1,3-nonadien-8-
ine that is obtained after chromatographic separation in Example
ld.
IR: 3420, 2931, 2856, 2221, 1708, 1600, 1490, 991 cm~l.
21 821 91
Example 4
(5R)-5-Fluoro-5- r cis-(2S)-2-((lE 3E~-(5R~-5-hydroxy-6 6-
trimethylene-9-phenyl-1 3-nonadien-8-inyl-(lS~-cyclohexyl]-
pentanoic acid diastereomer unPol ~12)
Analogously to Example 2, the title compound is obtained as
a colorless oil from the (5R)-5-fluoro-5-[cis-(2S)-2-(lE,3E)-
(5R)-5-acetoxy-6,6-trimethylene-9-phenyl-1,3-nonadien-8-inyl)-
(lS)-cyclohexyl]-pentan-l-ol-tert-butyldimethylsilyl ether that
is produced according to Example 1.
IR: 3400, 2935, 2860, 2220, 1710, 1600, 992 cm~1.
Example 5
5- r (E)-(2S)-2-((lE,3E)-(5R)-5-Hydroxy-5-cYclohexYl-1,3-
pentadienyl)-cyclohexylidenel-pentanoic acid diastereomer pol
(12)
Analogously to Example 1, 470 mg of 5-[(E)-(2S)-2-((lE,3E)-
(5R)-5-acetoxy-cyclohexyl-1,3-pentadienyl)-cyclohexylidene]-
pentan-l-ol-tert-butyldimethylsilyl ether, 350 mg of mixed
fractions, is obtained as a nonpolar component from 1.5 g of
(5S)-5-hydroxy-5-[cis-(2S)-2-((lE,3E)-(5R)-5-acetoxy-5-
cyclohexyl-1,3-pentadiene)-(lS)-cyclohexyl]-pentan-l-ol-tert-
butyldimethylsilyl ether (diastereomer pol (12)), and as a polar
component, 560 mg of (5R)-5-fluoro-5-[cis-(2S)-2-((lE,3E)-(5R)-5-
acetoxy-cyclohexyl-1,3-pentadienyl)-cyclohexyliden]pentan-1-ol-
tert-butyldimethylsilyl ether is obtained as colorless oils.
IR spectrum of the olefin: 2930, 2858, 1735, 1653, 1235,
1100, 990, 836 cm~~.
46 21 ~21 91
IR spectrum of the fluorine product: 2930, 2858, 1737,
1238, 1102, 99o, 938 cm-1.
Analogously to the silyl ether cleavage that is described in
Example 1, 270 mg of l-alcohol is obtained as a colorless oil
from 460 mg of the olefin, produced above. In addition, 60 mg of
the isomeric Z-configured ~5~6-olefin is separated here.
IR: 3450, 2923, 2858, 1733, 1236, 990, 972 cml.
Analogously to the oxidation of the 1-hydroxy group that is
described in Example 1, 140 mg of 1-carboxylic acid is obtained
as a colorless oil from 270 mg of 1-alcohol, produced above.
IR: 3500, 2936, 2860, 1726, 1245, 991 cm~1.
Analogously to the acetate saponification described in
Example 1, 118 mg of the title compound is obtained as a
colorless oil from 140 mg of carboxylic acid, produced above.
IR: 3400, 2925, 2850, 1708, 1450, 990 cm~1.
The starting material of the above title compound is
produced as follows:
5a) (5R)-5-Acetoxy-1-rcis-(lS)-1-hydroxYmethYl)-(2S)-cYclohex-2-
yl~-5-cyclohexyl-(lE,3E)-pentadiene diastereomer pol (12)
A solution of 26 g of dimethyl-(3-cyclohexyl-2-oxo-ethyl)-
phosphonate in 283 ml of dimethoxyethane is added in drops to a
suspension of 4.03 g of sodium hydride (65% suspension in oil) in
47
21 P~121 91
195 ml of dimethoxyethane at 0C, and it is stirred for 1 hour at
0C. Then, a solution of the aldehyde, described under lb, in
470 ml of dimethoxyethane is added in drops, stirred for 1 hour
at 0C, for 4 hours at 25C and then poured onto saturated
ammonium chloride solution. It is extracted three times with
diethyl ether, the organic phase is washed with water, dried on
magnesium sulfate and concentrated by evaporation in a vacuum.
The residue is purified by column chromatography on silica gel.
With hexane/diethyl ether (9+1), 35 g of the unsaturated ketone
is obtained as a colorless oil.
IR: 2923, 2850, 1673, 1660, 1630, 1593, 1000, 835 cm~1.
To reduce the keto group, 4.95 g of Ce(III)-chloride
heptahydrate is added to a solution of 34.6 g of the ketone,
described above, in 885 ml of methanol and 89 ml of
tetrahydrofuran at -60C, it is stirred for 15 minutes and then
mixed in portions with 5 g of sodium borohydride. It is stirred
for 15 minutes at -60C, mixed with 35 ml of acetone, stirred for
15 minutes, neutralized at room temperature with glacial acetic
acid and concentrated by evaporation in a vacuum. Then, the
residue is taken up in a diethyl ether/water mixture, the aqueous
phase is shaken with diethyl ether, the organic phase is washed
neutral with water, dried on sodium sulfate and concentrated by
evaporation in a vacuum. The residue is chromatographed several
times on silica gel. With hexane/diethyl ether (97+3), first
12 g of the nonpolar S-configured alcohol (5S)-5-hydroxy-1-[cis-
(lS)-1-(tert-butyl-dimethylsilyloxymethyl)-(2S)-cyclohex-2-yl]-5-
48 21821~1
cyclohexyl-(1E,3E)-pentadiene and 17 g of polar R-configured
alcohol (SR)-5-hydroxy-1-[cis-(lS)-l-(tert-butyl-
dimethylsilyloxymethyl)-(2S)-cyclohex-2-yl]-S-cyclohexyl-(lE,3E)-
pentadiene are obtained as colorless oils.
IR: 3340, 2920, 2850, 990, 838 cm~l.
Analogously to the acetylation described in Example ld),
17.4 g of the acetate is obtained as a colorless oil from 17 g of
the polar (5R)-configured alcohol, described above.
IR: 2930, 2860, 1725, 1250, 992, 975, 840 cm~1.
Analogously to the silyl ether cleavage described in Example
ld), 9.84 g of the alcohol is obtained as a colorless oil from
13 g of the acetate, described above.
IR: 3620, 3450, 2932, 2860, 1725, 1250, 993, 945 cm~1.
5b) (SS)-5-Hydroxy-5-rcis-(2S)-2-((lE,3E)-(5R)-5-acetoxY-5-
cYclohexyl-1,3-pentadiene)-(lS)-cyclohexyll-pentan-l-ol-tert-
butyldimethylsilyl ether fdiastereomer pol (12))
Analogously to Example le), the aldehyde, which is used
without further purification, is obtained from 9.84 g of the
alcohol, produced above under ld, with 77 g of Collins reagent.
Analogously to the Grignard reaction described in Example
le), first 2.35 g of the 5R-configured diastereomer alcohol is
obtained from 6.2 g of the aldehyde, produced above, in the case
of chromatographic separation, as well as 5.15 g of the SS-
49 21~2~1
configured diastereomer alcohol (title compound) as a polarcomponent.
IR: 3S70, 2922, 2852, 1729, 1244, 991, 836 cm~1.
ExamPle 6
(5R)-5-Fluoro-5-rcis-(2S)-2-((lE 3E)-(5R)-5-hydroxY-5-cyclohexyl-
1 3-pentadienyl)-(lS)-cYclohexyl~-pentanoic acid diastereomer
pol (12)
Analogously to Example 2, 33 mg of l-alcohol is obtained as
a colorless oil from 560 mg of the (5R)-5-fluoro-5-[cis-(2S)-2-
((lE,3E)-(5R)-5-acetoxy-cyclohexyl-1,3-pentadienyl)-
cyclohexylidene]-pentan-l-ol-tert-butyldimethylsilyl ether and
1.04 g of tetrabutylammonium fluoride, produced in Example 5.
IR: 3420, 2928, 2859, 1737, 1244, 992 cm~1.
Analogously to the oxidation of the alcohol to l-carboxylic
acid, described in Example 2, 230 mg of l-carboxylic acid is
obtained as a colorless oil from 330 mg of the alcohol produced
above.
IR: 3500, 2930, 2860, 1725, 1248, 992 cm~1.
Analogously to the acetate saponification described in
Example 2, 218 mg of the title compound is obtained as a
colorless oil from 230 mg of the l-carboxylic acid produced
above.
IR: 3480, 2923, 2852, 1737, 1450, 1170, 990, 952, 920 cm~1.
21821 91
ExamPle 7
5~ r (E)-(2S)-2-((lE,3E)-(5S)-5-hydroxy-5-cYclohexYl-1,3-
pentadienyl)-cyclohexylidene~-Pentanoic acid diastereomer unpol
(12)
Analogously to Examples 1 and 3, the title compound is
obtained as a colorless oil from the nonpolar S-configured
alcohol (5S)-5-hydroxy-1-[cis-(lS)-1-(tert-butyl-
dimethylsilyloxymethyl)-(2S)-cyclohex-2-yl]-5-cyclohexyl-(lE,3E)-
pentadiene that is obtained in Example 5a) after chromatographic
separation.
IR: 3400, 2927, 2852, 1708, 1451, 991 cm~1.
ExamPle 8
(5R)-5-Fluoro-5-~cis-(2S)-2-((lE,3E)-(5S)-5-hYdroxy-5-cyclohexyl-
1,3-pentadienyl)-(lS)-cyclohexyll-Pentanoic acid diastereomer
unpol (12)
Analogously to Examples 2 and 6, the title compound is
obtained as a colorless oil from the (5R)-5-fluoro-5-[cis-(2S)-2-
((lE,3E)-(5S)-5-acetoxy-cyclohexyl-1,3-pentadienyl)-
cyclohexylidene]-pentan-1-ol-tert-butyldimethylsilyl ether that
is produced according to Example 5.
IR: 3400, 2925, 2852, 1738, 1450, 1170, 990, 950, 920 cm~1.
51 2 1 82 1 ~ 1
Example 9
5-~(E)-(2S)-2-((lE,3E)-(5S)-5-Hydroxy-6,6-trimethylene-9-phenyl-
1,3-nonadien-8-inyl)-cYclohexylidene]-Pentanoic acid-methYl ester
diastereomer pol (12)
An ethereal diazomethane solution is added in drops to a
solution of 120 mg of the acid, produced according to Example 1,
in 4 ml of dichloromethane at 0C until permanent yellow
coloring, and it is stirred for 15 minutes at 0C. Then, it is
concentrated by evaporation in a vacuum, and the residue is
purified by column chromatography on silica gel. With
hexane/ethyl acetate (1+1), 116 mg of the title compound is
obtained as a colorless oil.
IR: 3472, 2928, 2853, 2200, 1738, 1442, 1246, 1160,
992 cm-1.
Example 10
5- r ( E)-(2S~-2-((lE,3E)-(5R)-5-Hydroxy-5-cyclohexyl-1,3-
pentadienyl)-cyclo-hexYlidene~-pentanoic acid methyl ester
diastereomer pol (12)
Analogously to Example 9, 160 mg of the title compound is
obtained as a colorless oil from 190 mg of the acid produced
according to Example 5.
IR: 3470, 2930, 2855, 1739, 992 cm1.
52 2l82
Example 11
5-~(E)-(2S)-2-((lE,3E~-(5S)-5-HYdroxy-6,6-trimethylene-9-phenYl-
1,3-nonadien-8-inyl~-cyclohexylidenel-pentanoic acid-(3-
hydroxypropylamide) diastereomer Pol (12)
450 mg of 3-amino-1-propanol is added to a solution of 250
mg of the methyl ester, produced according to Example 9, in 8 ml
of acetonitrile, and it is stirred for 24 hours at 50C and for
24 hours at 80C. Then, it is concentrated by evaporation in a
vacuum, and the residue is purified by column chromatography on
silica gel. With dichloromethane/methanol (9+1), 203 mg of the
title compound is obtained as a colorless oil.
IR: 3340, 2928, 2828, 1651, 1530, 990 cm1.
ExamPle 12
Tris-(hydroxymethyl)-aminomethane salt of 5-~(E)-(2S)-2-((lE,3E)-
(5S)-5-hYdroxy-6,6-trimethylene-9-phenyl-1,3-nonadien-8-inYl)-
cyclohexylidene]-pentanoic acid diastereomer Pol (12)
0.08 ml of an aqueous tris-(hydroxymethyl)aminomethane
solution (production: 8.225 g of trishydroxymethyl)aminomethane
is dissolved in 15 ml of water) is added to a solution of 150 mg
of the carboxylic acid, produced according to Example 1, in 24 ml
of acetonitrile at 80C, it is stirred for 1 hour at 80C, for 1
hour at 55C, for 3 hours at 45C and for 60 hours at 24C. The
crystals that are produced are suctioned off, washed with some
acetonitrile, and the crystals are dried at 24C in a vacuum. In
this case, 140 mg of the title compound is obtained as a waxy
compound.
2 1 Q~2 1 q 1
IR: 3320, 2922, 2852, 1550 (broad), 991 cm~1.
Example 13
s-r (E)-(2S)-2-((lE,3E)-(5S)-5-HYdroxY-6,6-dimethyl-9-Phenyl-1,3-
nonadien-8-inyl)-cyclohexylidene~-pentanoic acid diastereomer
pol (12)
Analogously to Example 1, 510 mg of 5-[(E)-(2S)-2-(tlE,3E)-
(5S)-5-acetoxy-6,6-dimethyl-9-phenyl-1,3-nonadien-8-inyl)-
cyclohexylidene]-pentan-l-ol-tert-butyldimethylsilyl ether, 390
mg of mixed fractions, is obtained as a nonpolar component from
1.6 g of (5S)-5-hydroxy-5-[cis-(2S)-2-((lE,3E)-(5S)-5-acetoxy-
6,6-dimethyl-9-phenyl-1,3-nonadien-8-inyl)-(lS)-cyclohexyl]-
pentan-l-ol-tert-butyldimethylsilyl ether (diastereomer pol (12))
and as a polar component, 410 mg of (SR)-5-fluoro-5-[cis-(2S)-2-
((lE,3E)-(5S)-5-acetoxy-6,6-dimethyl-9-phenyl-1,3-nonadien-8-
inyl)-(lS)-cyclohexyl]-pentan-1-ol-tert-butyldimethylsilyl ether
is obtained as a colorless oil.
IR spectrum of the olefin: 2931, 2860, 1730, 1250,
991 cm~1.
Analogously to the silyl ether cleavage that is described in
Example 1, 280 mg of l-alcohol is obtained as a colorless oil
from 510 mg of the olefin, produced above. In addition, 80 mg of
the isomeric Z-configured ~5~6-olefin is separated here.
IR: 3420, 2925, 2851, 2220, 1736, 1663, 1240, 992 cm~~.
54 2182t91
Analogously to the oxidation of the 1-hydroxy group that is
described in Example 1, 150 mg of 1-carboxylic acid is obtained
as a colorless oil from 280 mg of 1-alcohol produced above.
IR: 3510, 2936, 2860, 1729, 1245, 992 cm~1.
Analogously to the acetate saponification that is described
in Example 1, 122 mg of the title compound is obtained as a
colorless oil from 150 mg of the carboxylic acid produced above.
IR: 3410, 2930, 2856, 2220, 1710, 1600, 1490, 991 cm1.
The starting material for the above title compound is
produced analogously to the approach described in Example la-le).
The 2-oxo-3,3-dimethyl-6-phenyl-hex-5-ine-phosphonic acid
dimethyl ester that is required for the structure of the chain is
produced from isobutyric acid, however, analogously to Example
la).
Example 14
(5R)-5-Fluoro-5-~cis-(2S)-2-((lE,3E)-(5S~-5-hydroxY-6,6-dimethyl-
9-phenyl-1,3-nonadien-8-inyl)-(lS)-cyclohexyl~-pentanoic acid
diastereomer Pol (12)
Analogously to Example 2, 260 mg of 1-alcohol is obtained as
an oil from 410 mg of the (5R)-5-fluoro-5-[cis-(2S)-2-((lE,3E)-
(5S)-5-acetoxy-6,6-dimethyl-9-phenyl-1,3-nonadien-8-inyl)-(lS)-
cyclohexyl~-pentan-1-ol-tert-butyldimethylsilyl ether, produced
in Example 13, and 810 mg of tetrabutylammonium fluoride.
IR: 3450, 2930, 2860, 1740, 1245, 992 cm1.
2l~ 2l9l
Analogously to the oxidation of the alcohol, described in
Example 2, to 1-carboxylic acid, 180 mg of 1-carboxylic acid is
obtained as a colorless oil from 250 mg of the alcohol produced
above.
Analogously to the acetate saponification described in
Example 2, 145 mg of the title compound is obtained as a
colorless oil from 180 mg of 1-carboxylic acid produced above.
IR: 3430, 2935, 2863, 2200, 1710, 1599, 992 cm~1.
