Note: Descriptions are shown in the official language in which they were submitted.
PROCESS FOR PREPARING OPTICALLY ACTIVE IMIDAZOLYLPROPANOL
_
CO~IPOUNDS, AND INTERMEDIATE THEREIN
. . _ .
The present invention relates to a process for
preparing optically active imidazolylpropanol compounds, and
an intermediate therein.
The said optically active imidazolylpropanol
compounds are representable by the formula:
~N
N
C 2 ~ CH2-S-(CH2)n CH3
C ~ '-OH (I)
Cl
wherein n is an integer of 3 or 4.
The racemic mixture of an imidazolylpropanol
compound corresponding to the formula (I) is known to be
useful as an antifungal agent (cf. Japanese Patent
Publication (unexamined) No. 106666/1982). In order to
provide more active compounds, an extensive study has been
made, and it ha~ been found that the (R)-isomer o the
imidazolylpropanol compound (I) is highly active.
On Candida infection in mice, the said (R)-isomer
showed a more remarkable effect in decreasing mortality than
the corresponding racemate or (S)-isomer. Thus, the
(R)-lsomer is particularly useful as an antifungal agent.
..
5~
-- 2 --
The present invention provides a novel process for
preparing the optically active imidazolylpropanol compounds
of the formula tI), i.e. the ~R)-isomer, which may be
illustratively shown in the following scheme:
~;~
o
1H 2~
,~Cl
Cl (racemic)
(I~)
HS~ ~ Cl
(V)
I
- [~ y ~ O ~
CH2` ~ CH2-S-C ~ Cl ~ CH2 ~ CH2-S-C /S ~ Cl
110 -- ~ Cl Cl ~OH
C
(VIa) (VIb)
~9~jl5~
-- 3 --
(VIb )
~N ~ -
2 ~ 2
C l~f ' OH
Cl
(II)
.
CH3- (CH2~ n~X
(III)
~ /
(I).
In the above method, the racemic epoxide of the
formul.a (IV) is irst reacted with an optically active
thiolccarboxylic acid of the formula (V) in an inert solvent
at a température of from about -20 to 80C to give a 1:1
diastereomeric mixture of the thioloes~ers (VIa) and (VIb).
The racemic epoxide (VI) is known (cf. Japanese
Patent Publications (unexamined~ Nos. 12372/1981 and
106666/1982). The optically active thiolocarboxylic acid
(V) ca:n be prepared from the corresponding carhoxylic acid
chloride of the formula:
5~
O ~ ,H
Cl-ll~Cl
(J.Synthetic Organic Chemistry, Japan, 38, 1151-1162 (1980))
by reacting the latter with potassium or sodium hydrosulfide
in an inert solvent such as a hydrocarbon (e.g. benzene,
toluene) or an alcohol (e.g. methanol, ethanol~ at a
temperature of about -10 to 10C (cf. Org. Synthesis, Col.
Vol. III, p. 116). The optically active thiolocarboxylic
acid ~V) is merely a typical example, and other optically
active thiolocarboxylic acids such as (~ methoxy-~-tri-
fluoromethylphenyl~hioloacetic acid and L-menthoxythiolo-
ace~ic acid may be also used. These optically active
thiolocarboxylic acids are representable by the formula:
A-SH wherein A is an optically active acyl gxoup. Examples
of the inert solvent are hydrocarbons (e.g. n-hexane,
benzene, xylene~, alcohols ~e.g. methanol, ethanol,
isopropanol), halogenated hydrocarbons (e.~. dichloro-
methane, chloroform, 1,2-dichloroethane), ketones (e.g~
acetone, methyl ethyl ketone), ethers (e.g. diethyl ether,
t~trahydrofuran, dioxane), esters (e.g. ethyl ac tate),
amides (e.g. N,N-dimethylformamide, N,N-dimethylacetamide),
etc. The amount of the optically active thiolocarboxylic
acid (V) may be usually a molar equivalent or slightly
excess to the racemic epoxide (IV).
From the 1:1 diastereomeric mixture, the
(R)-isomer (VIb) is separa$ed and collected by a per se
5 --
conventional separation procedure such as fractional
crystallization. For the fractional crystallization, an
inert solvent such as an alcohol (e.g. methanol, ethanol,
isopropanol) or a hydrocarbon (e.g. n-hexane, b~nzene,
toluene, xylene) may be used.
The most straightforward procedure for obtaining
the desired (R)-isomer (VIb) comprises performing the
reaction between the racemic epoxide (IV) and the op-tically
active thiolocarboxylic acid (V) in a solvent usable for the
fractional crystallization. In such case, the crystals of
the (R)-isomer are separated out from the reaction system on
the completion of the reaction and can be readily collected
by filtration.
The separated (R)-isomer (VIb) is then treated
with a base in an inert solvent at a temperature of about
-lO to 100C in an inert atmosphere (e.g. nitrogen, argon)
to give the imidazolylthiol of the formula (II). As the
base, there may be used an alkali metal hydroxide (e.g.
lithium hydroxide, sodium hydroxide, potassium hydroxide),
an alkali metal carbonate (e.g. sodium carbonate, potassium
carbonate), an alkali metal alcoholate (e.g. sodium
ethylate, sodium methylate), an alkali metal sulfhydrate
(e.g. sodium sulfhydrate, potassium sulfhydrate), ammonia,
organic amines (e.g. monomethylamine, diethylamine,
triethylamine), etc. Examples of the inert solvent are
water, alcohols (e.g. methanol, ethanol, isopropanol),
ketones (e.g. acetone, methyl ethyl ketone), ethers (diethyl
B5~
-- 6 --
ether, tetrah~drofuran~ dioxane), amides (e.g. N,N-dimethyl-
formamide, N,N-dimethylacetamide), etc. Their mixtures are
also usable. The amount of the base is usually not less
than l mole, preferably from 1 to 20 moles, per mole of the
(~)-isomer (VIb).
Then, the imidazolylthiol (II) is reacted with an
alkylating agent of the formula (III), preferably in the
presence of a base in an inert solvent to give the objective
optically active imidazolylpropanol compound (I). In the
formula (III) for the alkylating agent, X represents a
halogen atom (e.gO chlorine, bromine, iodine), an alkyl-
sulfonyloxy group le.g. methanesulfonylo~y) or an aryl-
sulfonyloxy group (e.g. benzenesulfonyloxy, toluene-
sulfonyloxy). Examples of the base are an alkali metal
hydroxide (e.g. lithium hydroxide, sodium hydroxide,
potassium hydroxide), an alkali metal carbonate (e.g. sodium
carbonate, potassium carbonate), an alkali metal (e.g.
lithium, sodium, potassium), an alkali metal hydride (e.g.
sodium hydride), a tertiary amine (e.g. pyridine,
triethylamine), etc. As the inert solvent, there may be
used a hydrocarbon (e.g. benzene, toluene, xylene), a
chlorinated hydrocarbon (e.g. methylene chloride, chloro-
form, 1,2-dichloroethane), an alcohol (e.g. methanol,
ethanol, isopropanol), a ketone (e.g. acetone, methyl ethyl
ketone), an ether (e.g. diethyl ether, tetrahydrofuran,
dio~.ane), an ester (e.g. ethyl acetate), an amide (e.g. N,N-
dimethylformamide, N,N-dimethylacetamide), water, etc. The
35~
amount of the alkylating agent (III) may be more than 1
mole, preferably 1 to 10 moles, per mole of the imidazolyl-
thiol (II). The amount of the base is usually more than 1
mole, preferably 1 to 30 moles, per mole of the imidazolyl-
thiol (II). The rèaction temperature is usual:Ly above
-20C, preferably from -20 to 100C.
The optically active imidazolylpropanol compound
(I) can be prepared more conveniently and advantageously by
treating the (R)-isomer (VIb) successively with -the base and
with the alkylating agent (III~ in a single reaction vessel
without isolation of the intermediarily produced imidazolyl-
thiol (II).
The manner for recovery of the optically active
imidazolylpropanol compound (I) from the reaction mixture
depends upon the property of the reac-tants as used, but in
general, the reaction mixture is subjected to evaporation of
the solvent, dilution of the residue with water and extrac-
tion of the objective optically active imidazolylpropanol
compound (I) with an appropriate water-immiscible solvent.
The thus produced optically active imidazolyl-
propanol compound (I) may be converted into its acid
add.ition salt by treatment with an acid (e.g. hydrochloric
acid t hydrobromic acid, phosphoric acid, nitric acid, acetic
acid, maleic acid, succinic acid, fumaric acid, tartaric
acid, citric acid, salicylic acid, sorbic acid, lactic acid,
oxaLic acid).
The optically active imidazolylpropanol compounds
-- 8 --
of the formula (I) are usually administered to pa-tients
orally or parenterally and are ordinarily employed in the
form of a pharmaceutical composition which contains them in
an effective and non-toxic amount in admixture with
conventional pharmaceutical carrier materials suitable for
oral or parenteral application and being unreactive with the
active compounds. The pharmaceutical composition may be in
the dosage form of tablets, capsules, granules, fine
granules, powders, syrups, suspensions, emulsions, supposi-
tories, injections, or the like. These pharmaceutical
compositions can be prepared by conventional methods by
us:ing conventional carrier materials, excipients, binding
agents, stabilizers, etc. For injection, the preparation
may be prepared by dissolving the active compounds in
purified water for injection, which may optionally contain
other additives, such as isotonic agen-ts (e.g. glucose,
saline~, buffexing agents, solubilizers, pH adjusting agents
or preservatives.
The dosage of the optically active imidazolyl-
propanol compounds (I) may vary with the administration
rou~es, the age and weight of the patient, the kinds and
severity of the diseases to be treated, or the like. In
case of oral administration in adult, it is usually used in
an amount of 50 to 1,000 mg, preferably of 100 to 500 mg,
~er day, which may be administered once a day but may also
be divided and administered in two to several times per day.
In case of injection in adult, it is usually used in an
356
amount of 10 to 400 mg, preferably 20 to 200 mg, per day,
~hlch may be administered once a day but may also be divided
and administered in two to several times per clay.
Practical and presently preferred embodiments for
production of the compounds (I) are illustratively shown in
the following Examples.
Example 1
.
Preparation of (R)-3-[(S)-2-(4-chlorophenyl)iso-
valerylthio]-2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-2-
propanol (VIb)o-
To a solution of dl-2-(2,4-dichlorophenyl)-2-
(imidazol-l-yl)methyloxirane (IV) (269 y) in toluene (1100
ml) was added (S)-2-(4-chlorophenyl)thioloisovaleric acid
(V) (229 g) obtained in Reference Example 5 at room
temperature. The mixture was stirred without external
cooling, while the temperature raised spontaneously to 55C
during the first 10 minutes. The mixture was kept at the
same temperarture as above for another 1 hour and then at
20C for 3 hours. The precipitate was collected by
filtration, washed successively with toluene and isopropanol
and dried in vacuo to give (R)-3-[(S)-2-(4-chlorophenyl)iso
valerylthio]-2-(2,4-dichlorophenyl)-1-(imidazol-1 yl)-2~
propanol (VIb) (204 g). Yield, 41 ~. M.P., 182 - 183C.
[a]23 -1.0 (c = 1, methanol).
Example 2
Preparation of (R)-2-(2j4-dichlorophenyl)-1-
(imidazol-l-yl)-3-mercapto-2-propanol (II):-
~3~
-- 10 --
To a suspension o~ the compound (VIb~ [49.5 g)obtained in Example 1 in toluene (300 ml) was added a 10 %
me-thanolic potassium hydroxide solution (160 g) at a
temperature of -5C to 0C in nitrogen atmosphere. The
mixture was warmed to 25C over a peîiod of about 30 minutes
and stirred at the same temperature for 2 hours. The
reaction mixture was concentrated under reduced pressure.
The residue was dissolved ln dichloromethane (300 ml),
washed with water, dried and evaporated to give an oil. The
oil was purified by silica gel column chromatography using
chloroform as an eluent and recrystallized from a mixture of
dichloromethane and n-he~ane to give (R)-2-(2,4-dichloro-
phenyl)-1-(imidazol-1-yl)-3-mercapto-2-propanol (II) t9.4
g). Yield, 31 %. M.P., 155 - 157C. [~]D -6.6 (c = 1,
methanol).
Example 3
Preparation of (R)-2-(2,4-dichlorophenyl)-1-
(imidazol-l-yl)-3-mercapto-2-propanol (II):-
~ In the same manner as in Example 2 but using 10 %
water-containing methanol (400 ml~ and sodium sulfhydrate
(10 g) in place of methanol and potassium hydroxide,
respectively, there was obtained (R)-2-(2,4-dichlorophenyl)-
l-(imidazol-l-yl~-3-mercapt~-2-propanol (II) (11.3 g).
Yield, 37 %. M.P., 156 - 157C. [~]D4 ~7 0 (c = 1,
methanol).
Example 4
- l l -
Preparation of (R)-3-(n-butylthio)--2-(2,4-di-
chlorophenyl)-l-(imidazol l-yl)-2-propanol (I: n = 3)
hydrochloride:-
To a solution of sodium hydro~ide (2 ~) inmethanol (100 ml) were added n-butylbromide (2 g) and (~)-2-
(2,4-dichlorophenyl)-1-(imidazol-1-yl)-3-mercapto-2-propanol
(II) obtained in Example 2 at a temperature of 20 - 25C in
nitrogen atmosphere. The mixture was stirred at 25 - 30C
for 5 hours and then concentrated under reduced pressure.
The residue was treated with water (50 ml) and extracted
with dichloromethane (50 ml). The extract was washed with
water, dried over anhydrous magnesium sulfate and concen-
trated to give an oil. The oil was dissolved in diethyl
ether (20 ml), and hydrogen chloride gas was introduced
thereto. Precipitated crystals were collected by filtration
and dried to give (R)-3-(n-butylthio)-2~(2,4-dichloro-
phenyl)-1-(imidazol-1-yl)-2-propanol (I: n = 3) hydro-
chloride (3.4 g). Yield, 86.8 %. M.P., 168 - 169C. [~]20
-89.7 (c = 1, methanol). The optical purity of the product
was not less than 99 % determined by high performance liquid
chromatography.
Example 5
Preparation of ~R)-3-(n-butylthio)-2-(2,4-di-
chlorophenyl) l-(imida~ol-l-yl)-2-propanol (I: n = 3)
hydrochloride:-
T~ a solution of (R)-2-(2,4-dichlorophenyl)-1-
limidazol-l-yl)-3-mercapto-2-propanol (II) t3 g) in dxy N,N-
56
- 12 -
dimeth~lformamide (20 ml) were added a 50 ~ dispersion of
sodium hydride iII paraffin (1 g) and n-butyl p-toluene-
sulfonate (2.3 g) at 0 - 5C in nitroclen atmosphere. The
rnixture was stirred at 0 - 5C for 1 hour and at 20 - 25C
for 18 hours. The reactlon mixture was diluted wi-th water
(200 ml) and extracted with dichloromethane. Treatment of
the extract in the same manner as in Example 4 gave (R)-
3-(n-butylthio)-2-(2,4-dichlorophenyl)-1-(imidazol-l-
yl)-2-propanol (I: n = 3) hydrochloride (2.5 g). Yield,
63.8 ~. M.P., 168 - 169C. [~]20 -88.8 ~c = l, methanol).
E~ample 6
Preparation of (R)-3-(n-butylthio)-2-(2,4-di-
chlorophenyl)-l-~imidazol-l-yl)-2-propanol (I: n = 3)
hydrochloride:-
To a suspension of (R)-3-[(S)-2-(4-chlorophenyl)-
isovalerylthio]-2-(2,4 dichlorophenyl)-1-(imidazol-1-yl)-2-
propanol (VIb) (49.5 g) obtained in Example 1 in methanol
(S00 ml) were added a 10 r~ methanolic potassium hydroxide
solution (240 g) and n-butylbromide (21.6 g) at -5 to 0C in
nitrogen atmosphere. The slurry was stirred at the same
temperature for 2 hours and then at 30C for 3 hours.
Methanol was removed by distillation under atmospheric
pressure, and the residue was treated with water (200 ml~
and extracted with 1,2-dichloroethane (200 ml). The extract
was washed successively with water and 12 ~ hydrochloric
acid (200 ml) and concentrated in vacuo. To the residue
were added toluene (100 ml) and methyl ethyl ketone (35 ml),
and the slurry was stirred at 15C for 3 hours. Filtration
and drying in vacuo gave a crude product (25.7 g), which was
recrystallized from methyl ethyl ~etone to give (R)-3-(n-
butylthio)-2-(2,4-dichlorophenyl) 1-(imidazol-1-yl)-2-
propanol (I: n = 3) hydrochloride (21.8 g) as colorless
needle.s. Yield, 55 %. M.P., 168.5 - 170C. [~]20 -S9.8
(c = 1, methanol).
Reference Exa~ple 1
Preparation of (S)-2-(4-chlorophenyl)thioloiso-
valeric acid (V):-
To a solution of potassium hydroxide (296 g) inmethanol (1500 ml) was introduced hydrogen sulfide gas (180
g) from a gas-inlet tube at a temperature below 30C, and
the mixture was cooled at -5C. A solution of (S)-2-(4-
chlorophenyl)isovaleryl chloride (510 g) in toluene (1000
ml) was dropwise added thereto at a temperature of -5 to
10C. The mixture was stirred at the same temperature for
30 minutes, followed by addition of water ~2000 ml). A 35 %
hydrochloric acid (455 g) was dropwise added thereto. The
toluene layer was washed with water ~500 ml) and concen-
trated in vacuo to give (S)-2-(4-chlorophenyl)thioloiso-
valeric acid (V) (504 g), which was used for the Eeaction in
Example 1 without purification.
The optically active imidazolylpropanols (I)
exhibit a remarkable antimicrobial activity against various
microorsanisms, particularly fungi. Also, some of them show
an antifungal activity against phytopathogenic fungi.
5~
- 14 -
A~vantageously, the optically active imidazolyl-
propanol compounds (I) are quite low in toxicity, and their
LD50 values are more than 500 mg/lcg when de-termined by oral
route to mice. Thus, they are useful as antiEungal agents.
The optically active imidazolylpropanol compounds
(I) can be administered parenterally, orally or locally to
warm-blooded animals and human beings in the form of
conventional pharmaceutical preparations. For instance,
they can be administred in the form of conventional solid
pharmaceutical preparations such as tablets, capsules,
powders or granules, or in the form of conventional liquid
pharmaceutical preparations such as suspensions, emulsions
or solutions. The daily dosage may vary depending upon the
administratlon route and is usually between 10 mg and 5 g
for human beings.
