Note: Descriptions are shown in the official language in which they were submitted.
WW-0027
l-PHENETHYLIMIDAZOLE DERIVATIVES
-
I. Description:
This invention relates to certain novel l-
phenethylimidazole derivatives and their antimicrobial
acid addition salts, antimicrobial compositions
containing the same, and methods of employing such
derivatives, salts and compositions for inhibiting
the growth of fungi and bacteria.
A large number of antifungal and antibacterial
agents have been previously described which contain a
~ aryl)ethyl-lH-imidazole moiety of the formula: ~
N
N
1 CH -CH-R
- 2 1 a
For example, in U.S. 3,7i7,655 and E. F. Godefroi
et al, J. Med. Chem. 12, 784 (1969), compounds of
formula 1 are disclosed in which Ra is:
-X(CH2)n-
wherein X is O or NH
-2~ 5 ~ ~ 7
In U.S. 3,991,201 and J. Heeres et al, J. Med.
Chem. 20, 1511 (1977), ~uch compounds are disclosed
in which Ra is -(CH2)n-Ar.
In J. Heeres et al, J. Med. Chem. 20, 1516 (1977),
such compounds are disclosed in which Ra is -(CH2)nO-Ar.
In U.S. 4,055,652 and 4,039,677, such compounds
are disclosed in which Ra is -SR2 wherein R2 is H,
benzyl, phenyl, etc.
In U.S. 4,039,677 and 4,038,409, such compounds
are disclosed in which Ra is -XICl-R3
wherein X and Y are O or S and R3 is H, alkyl, cycloalkyl,
phenalkyl, phenalkenyl, or -XR4 wherein R4 is alkyl,
halophenyl, etc.
In U.S. 4,006,243, such compounds are disclosed
in which Ra is H, alkyl or phenyl.
An entirely new class of compounds of formula 1
has now been discovered which have very good anti-
fungal and antibacterial activity, namely those in which
Ra is an optionally nuclearly substituted group of the
formula~
A -X-(CH2)n-Y-(CH2)m ~
wherein X and Y are independently sulfur or oxygen, m
is zero or 1 and n is 1, 2 or 3, with the proviso that
when n=l, X and Y cannot both be oxygen, and the CH
bonded phenyl ring is also optionally nuclearly sub-
stituted, and including the antimicrobial acid additionsalts of such compounds.
The products of the present invention are named
as derivatives of l-(ethyl)-lH-imidazole with the
substituents Rl and R2 located at position 2 of the
ethyl side chain, as in the following formula 2:
1 ~S~a ~
--3--
2 ~ ~
Il 2
CH2 FH- Rl
R2
Alternatively, the products can be named as
derivatives of l-(phenethyl)-lH-imidazole where the
substituent Rl is attached 3 to the imidazole ring,
as in the following formula 3: .
I ~
3 CH2CH-Rl
As indicated above, a primary feature of the present
invention is the provision of novel compounds of formula
1 above in which Ra has the formula A above and the CH
bonded phenyl ring is optionally nuclearly substituted,
and including the antimicrobial, i.e. antifungal and
antibacterial, acid addition salts of such compounds,
especially compounds of the formula:
4 c~f~-x (C~2,n~Y~(C~2,. ~ F~2
R5 - ~
R6
~1 5~ 7
including the antimicrobial acid addition salts thereof,
wherein:
X and Y are independently sulfur or oxygen; m is zero
or l; n is l, 2 or 3, with the proviso that when n=l, X
and Y cannot be both oxygen; Rl and R2 are independently
hydrogen, halogen or alkyl or taken together the atoms
necessary to complete a naphthalene ring; R3 is hydrogen,
halogen such as chlorine or fluorine, CF3, SCF3, alkyl,
alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, pyrrolidinyl,
piperidinyl, piperazinyl, alkanoylpiperazinyl, morpholinyl,
alkylamino, dialkylamino, alkanoylamino, amino, nitro,
carboxy, carboalkoxy or an aryl radical selected from the
group consisting of phenyl, benzyl, benzoyl, phenylthio,
phenylsulfonyl, phenylamino and benzoylamino, said aryl
radical being optionally nuclearly substituted by one or
more halogen, CF3, alkyl or alkoxy radicals' and R4, R5
and R6 are independently hydrogen, halogen, CF3, alkyl,
alkoxy or phenyl optionally nuclearly substituted by one or
more halogen, CF3, alkyl or alkoxy radicals;
and wherein with reference to the above, alkyl,
alkoxy and alkanoyl radicals contain 1 to 6 carbon atoms,
alkenyl and alkynyl radicals contain 2 to 12 carbon atoms,
and cycloalkyl radicals contain 5 to 8 carbon atoms.
The subject compounds of formula 4 above exhibit
antifungal and antibacterial activity against animal
and human pathogens as well as antifungal activity against
fungi of primarily agricultural importance. Thus, the
subject compounds are found to be u-seful antimicrobials,
having not only pharmaceutical but also agricultural
and industrial applications. Thus, a further feature
of the present invention relates to methods of inhibiting
the growth of fungi and bacteria
-- 4 --
~.
by applyin~ to a host object containing, or subject to
attack by, fungi or bacteria, a fungicidally or
bactericidally effective amount of a compound of
this invention. A still further feature of the
S present invention relates to compositions for pharma-
ceutical, agricultural, and industrial use, which
compositions comprise the subject compounds of formula
4 in combination with a suitable carrier.
Preferred embodiments of the invention include
1-phenethylimidazole compounds of the formula:
~3
N
CH2CHSCH2SCH2-Z
~ ~4 (I)
~'
R5
wherein R4 and R5 are independently hydrogen or halogen, and
Z is a mono or disubstituted phenyl moiety of the formula:
~ R2
wherein Rl and R2 are independently hydrogen, halogen, (lower)
alkyl, or trifluoromethyl, with the proviso that Rl and R2 can
not both be trifluoromethyl and the antimicrobial acid addition
salts thereof.
,. ,~
.
-5~-
Still another eature of this invention ~ 8 the
provision of compounds useful as intermediates for pro-
ducing the compounds of formula 4 above, such inter-
mediates having the formula:
N
CH2( 'H-X(CH2)n- Z
B
R4
R5~ ~~R6
wherein Z is a member selected from the group con-
sisting of YM, halo, COOalkyl, methanesulfonate and
-S2 ~ CH3, M is ~ or alkali metal, and X, Y, R4,
R , and R and n have the values defined above.
As employed herein and in the appended claims,
~alkyl", "alkoxy" and "alkanoyl" groups contain a
saturated, branched or unbranched acyclic hydro-
carbon group of 1 to about 6 carbon atoms, such as
methyl, ethyl, propyl, butyl, pentyl and hexyl and
isomeric forms thereof. I'Alkenyl'' groups contain a
branched or unbranched acyclic hydrocarbon group
,
j,
--6--
having carbon-carbon double bond unsaturation and
about 2 to about 12 carbon atoms such as allyl
ethenyl, 2-hexenyl, 3-octenyl, 2-octenyl, 2-decenyl,
l-dodecenyl and the like. "Alkynyl" groups are
similar to "alkenyl" but with carbon-carbon triple
bonds instead of double bonds. "Cycloalkyl" groups
contain a saturated monocyclic hydrocarbon group of
about 5 to about 8 carbons such as cyclopentyl,
cyclohexyl, cycloheptyl and cyclooctyl. "Halogen"
or "halo" refers to iodo, fluoro, bromo and most
preferably chloro. The term "antimicrobial acid
addition salts" refers to the crystalline salts
of the subject compounds which possess the desired
antimicrobial activity and which are neither
biologically nor otherwise undesirable. Such
salts are formed by contacting the subject compounds
with inorganic acids such as hydrochloric, hydrobromic,
hydroiodic, nitric, sulfuric and phosphoric acids, and
organic acids such as fumaric, oxalic, maleic, acetic,
pyruvic, citric, tartaric, methanesulfonic, ethane-
sulfonic, p-toluenesulfonic, hydroxyethanesulfonic,
sulfamic, malic, succinic, ascorbic, levulinic,
propionic, glycolic, benzoic, mandelic, salicylic,
lactic, p-aminosalicylic, 2-phenoxybenzoic, 2-acetoxy-
benzoic, 1,4-naphthalene disulfonic acids and the like.
The subject compounds of formula 4 are organic
bases, the majority of which are viscous oils in the
free base form. The free bases are usually purified
by column chromatography on either silicic acid or
alumina and may then be converted to their solid
acid addition salts by contacting them with one of
the above salt-forming acids, usually in a solvent such
, 1'~;~S~ ~
as water, ethanol, l-propanol, ethyl acetate, ace-
tonitrile or diethyl ether. Upon cooling or dilution
with a less polar solvent the acid addition salts
usually crystallize.
Such compounds of formula 4 contain a chiral or
asymmetric center, i.e. the carbon atom in the
depicted CH link, and therefore may exist as enantiomers
which may if desired be separated by known procedures
such as by conventional resolution means employing
optically active acids such as the optically active
forms of camphor-10-sulfonic, ~-bromocamphor-~-sulfonic,
camphoric, menthoxyacetic, tartaric, malic, di-
acetyltartaric, pyrrolidone-5-carboxylic acids and
the like. It will be understood that this invention
is inclusive of such optical isomers and the racemic
mixtures thereof.
PREPARATION OF ANTIMICROBIAL PRODUCTS
The compounds of formula 4 are prepared utilizing
the inherent variations of the Williamson Ether
Synthesis (Houben-Weyl, Methoden Der Organischen
Chemie, VI (Part 3)1975~.
As shown in Scheme I tosylate 5 is reacted with
phenoxides (6, m=O, Y=O), thiophenoxides t6, m=O, Y=S),
or the sodium or lithium salts of benzyl alcohols
(6, m=l, Y=O) or benzyl mercaptans (6, m=l, Y=S)
to provide the ethers 7 ~Y=O or S, m=O or 1).
Similarly, tosylate 8 has been reacted with
thiophenoxides (9) to afford the dithio ethers 10.
11~S~'7
--8--
~
~.
:C
-
C `
~J
~Z~
l ~
Z~Z_~
~D ~
U~
+ Z+ ~ I
o o
~ I ~ O ~ I ~D
U~
~ ~ ~r
~\z~ z-~ ~
5 7
g
Sch can be combined as follows:
Rl, 2, 3
CII~C~I-X-C~12CE12S2~ C~13+6 '> CH211 -X-CEl2cH2-y-(c l2)
~3R4 ~ 5 ~ 6 \ R'4' 5 ~ 6
Formation of the ethexs _ is accomplished by
intimately contacting a solution of the tosylate
11 in an inert solvent such as tetrahydrofuran
or tetrahydrofuran/N,N-dimethylformamide mixture,
with an alkali metal salt 6 (sodium or lithium) of
the requisite alcohol or mercaptan, usually in the same
solvent, or containing an additional co-solvent at
temperatures of about 25-100C and for periods of about
1 hour to several days. Of course the optimum
temperatures and times will vary according to the
nucleophilicity of the alcohol or mercaptan salt 6.
Preparation of the alkali metal salt 6 is effected
by contacting the alcohol or mercaptan with a base
such as sodium hydride and the like or n-butyl lithium
in the presence of organic solvents such as tetra-
hydrofuran and N,N-dimethylformamide at temperatures
of from -78C, when n-butyl lithium is used, and
about 0-100C when sodium hydride is used, and for
periods of about 15 minutes to several hours.
Additional suitable solvents for the formation
of the alkali metal salts 6, as well as for running
-
the reaction 11 ~ 12 include benzene, diglyme,
hexamethylphosphoramide, dimethoxyethane and toluene.
--10--
Additional leaving groups as alternatives to the
r
p-toluenesulfonate anion (13, Z = -OS02- ~ CH3)
include such conventional leaving groups as Z = chloro,
bromo, iodo, methanesulfonate and the like.
CN~
x c~12c~l2z
4,5,6
13
Alcohol 14, from which tosylate 5 is derived, has
been alkylated with benzyl halides 15, as shown in Scheme II, to
ethers 16, thus confirming that the roles of alcohol
and alkylating species can be interchanged in Williamson
Synthesis.
Alcohol 17, from which tosylate 8 is derived, may
be alkylated with the benzyl halides 15 to provide the
ethers 18.
_Sche;ne II;
R~ 3
C~12CI~OC-12 2 (C~2)m~3
~4, 5, 6 Z-CI"3r [~4, 5, 6
14 m--l
5 v ~ ~
Schcm~ I I ( Con~2
12C~ISC112C~120}1 2. 15 ;3~ ~}~2Ci~sc}~2c~-20
\<R45,6 ~\R 4 ,5,6
17 18
The alkylating agents 15 are added either neat or in
solution to a preformed alkali metal salt (preferably
sodium, but may be lithium or potassium) of alcohol
_ in a suitable solvent at about 0. The resulting
mixture is then heated at 25-100 to accelerate
the rate of reaction for periods of 30 min. to 24
hours. With the reactive benzyl halides the
reaction is complete in about 1-2 hours at about
60. Suitable solvents or solvent mixtures
include tetrahydrofuran, N,N-dimethylformamide,
hexamethylphosphoramide, benzene, toluene, diglyme,
dimethoxyethane and the like. The alkali me~al
salts of 14 are formed by contacting 14 with a
strong base, e.g. sodium hydride and the like in
the above solvents at 0-100 for periods of 15 min.
to several hours.
Products 22 of this invention may be synthesized as
shown in Scheme III.
1 ~ 7 ~ 7
Scheme II I
_
~1' (C2H)2 C
~ 4,5,6 l ~R4 5,6
20 + Z- (CH2) ~ ~-Y (CH2) m~
21 ~N~ pl,2,3
or 2CHS (CH2)n-Y-(CH
- C2~5~l ~ 22
~4,5,6
U.S. 4,038,409 and 4,039,677 disclose the
general methodology for the synthesis of the
required xanthate salt 19 and for its hydrolysis
to give thiol salt 20, which is then utilized in
the instant syntheses.
Thiol salt 20 is advantageously stockpiled as
the solid xanthate 19 and is generated in situ as
needed, under nitrogen to minimize oxidation. The
alkylating species 21 are then introduced and the
mixture stirred at 25-80 for periods of 0. 5-24 hours
to afford the desired products 22.
~ 1~50~7
-13-
The reaction of 20 with 21 (n=2, Z-Cl, Y=S) resulted
largely in eliminating of HCl from 21 to afford 23.
Rl,2,3 _ ~ SCH=CR2
23
Compounds of type 22 where n=2, Y=S and m=O are therefore
best synthesized according to the procedure outlined in
Scheme I.
As shown in Scheme IV, al~ylation of 24 with chloro-
methyl phenyl ulfides (21, Z=Cl, n=l, Y~S, m=O) or
benzyl chloromethyl sulfides (21, Z=Cl, n=l, Y=S, m=1)
provides the corresponding ethers 25 (n=l, Y=5, m=O or
10 1).
Scheme IV
C~ ¢ ~ ~ ,2,3
~3 ~ 21 ~ C~12Ci!O-(C~2)~~Y~(CH2)m <
,5,6 ~ 25
2~ \p4,5,6
Ethers of general structure 25, wherein n=2, Y=O and
m=O are preferably synthesized according to the procedure
outlined in Scheme I.
-
tj~ 7
-13a-
In a preferred process the compounds of formula I
are prepared as shown in the following chart.
1H~C~SCOC2H5 C~N ~ e e
(II) ~ N
(III) + CICH SCH - Z ~ l
2 2CH2CHSCH2SCH2 - Z
(IV)~ 4
(I)
The starting xanthates II and their acid addition salts
are known compounds and are readily prepared and hydrolyzed
to afford the thiol salts III by the procedures disclosed in
U.S. Pat. Nos. 4,038,409 and 4,039,677. The hydrolysis of
the Xanthate II or an acid addition salt of the xanthate II
and the subsequent alkylation of the thiol salt III are
usually conducted under an atmosphere of nitrogen to
minimize oxidation. To the resulting alcoholic solution of
the thiol salt III is added an approximately equimolar amount
of the appropriately substituted chloromethyl arylmethyl
sulfide IV, (Z=phenyl or thienyl). The reaction mixture is
then stirred for periods of about 1-24 hours at temperatures
of about 20 - 80C. Removal of the solvent leaves the crude
,. ~
~.~
11S5857
-13b-
product I, which is usually a viscous oil. The oil can be
purified by conversion to a solid acid addition salt, which is
then recrystallized, or the oil can be purified by chromato-
graphic techniques using silicic acid or alumina. If de-
sired, the purified oils can then be converted to suitableacid addition salts by methods commonly employed in the art.
Although we prefer ~o use the xanthates II and the
chloromethyl arylmethyl sulfides IV (Z=phenyl or thienyl) in
the instant syntheses, the preferred compounds I can also be
prepared according to the following general procedure:
N
CH2CH--S--W -- > 1H2CH--SM
R4 ~/~5~ ~R4
R (~I )
(V)
(VI) + L-CH2SCH2 - Z > (I)
(VII)
wherein W is a group which when treated with an alkali metal
hydroxide (M=sodium, lithium, potassium), in the presence of
a suitable solvent, is cleaved by hydrolysis to afford the
alkali metal thiolates VI. W, for example, can be one of the
groups disclosed in U.S. Pat. Nos. 4,038,409 and 4,039,677,
`. 1
;'
1 155857
-13c-
or can be a group such as, for example, amidino hydrochloride
: ~ NH
- C \ .HCl
NH2
or N-methyl-2-pyridinium chloride
'~1
1H3C1 e~
Treatment of the metal thiolate VI with the alkylating
species VII, wherein L is a conventional leaving group such as
halo (preferably chloro) mesyloxy or tosyloxy, in the presence
of a suitable inert solvent, affords the products I. The
starting compounds V, wherein M = amidino hydrochloride or
N-methyl 2-pyridinium chloride, can be prepared by con~acting
an imidazole of formula VIII in the presence of a suitable
solvent with thiourea or N-methyl-2(1~I)-pyridine thione,
respectively.
r N
~ N
I
CH2cH-cl (VIII)
~ R4
:
1~55857
-13d-
The l~ chlorophenethyl)imidazoles VIII are known
compounds and are described in ~.S. Pat. No. 3,679,697. As
depicted below, the preferred compounds I can also be pre-
pared by contacting an imidazole of formula VIII with a
hemi-mercaptal of formula IX, in the presence of an inert
solvent such as methanol, ethanol, N,N-dimethylformamide,
benzene, toluene and the like, containing an acid binding
agent such as sodium or potassium carbonate.
(VIII3 + HSCH2SCH2 - Z ) (I)
(IX)
Alternatively, the alkali metal salt of IX can be
preformed with bases such as sodium ethoxide, sodium methoxide
or an alkali metal hydride such as sodium hydride and the
preformed salt of IX contacted with VIII preferably in the same
solvent in which it was formed, to yield the sub~ect compounds
I. The hemi-mercaptals IX are prepared by the procedure of H.
15 Bohme, H. Fischer and R. Frank [Ann. Chem. 563, 54, (1949)]
which essentially consists of treating a chloromethyl sulfide,
such as IV with potassium sulfhydrate at low temperature.
Several of the chloromethyl arylmethyl sulfides IV
(Zs phenyl or thienyl) are described in the prior art. Those
which are not previously described can be prepared by well-
established techniques. For example, a mercaptan with the
formula HSCH2 Z, is treated with hydrogen chloride and
formaldehyde to afford IV, or the procedure of Goralski and
Burk [J. Org. Chem., 42,3094(1977)] can be utilized, in which
a mixture of the mercaptan, HSCH2 Z, in bromochloromethane
C~
~155857
-13e-
is stirred with powdered potassium hydroxide and a phase
transfer catalyst to afford IV after workup.
~,,,~
1 1S5857
-14-
PREPARATION OF INTE~.DIAT~S
Alcohol~ and Tosylates
Starting from the know alcohol 26, the novel ester
28, alcohol 14 and its corresponding tosylate 5 are
prepared as shown in Scheme V.
Scheme V
2 ~rCE2CD2C H > ~ ~ 4 ) ~ \~
H2CHOH CE~2CHOCH2C02C2H5 CH2,~HOCH2CH2-OH
4,5,6 ~ p~4,5,6 ~ ~ p4,5,6
C~3 ~ SO2C
N 3 TEa, CE12C12
CH2CHC~I2C~I2S2 ~ CH3
~4,5,6
Treatment of the anion of 26 (see U.S. 3,717,655
and Godefroi et al, supra for this and other operative
alcohols) with ethyl bromoacetate 27 proceeds
smoothly to give ester 28. The ester may be isolated
and purified as the solid nitrate salt, or can be
-15- i 155857
reduced, in a crude state, with lithium aluminum
hydride to provide the starting alcohol 14. Other
hydride reducing agents such as aluminum hydride,
diisobutylaluminum hydride and sodium bis(2-methoxy-
ethoxy) aluminum hydride and the like may be employed.Diethyl ether, tetrahydrofuran, diglyme and benzene
are suitable solvents.
Alcohol 14 is a viscous gum and is isolated,
purified and stockpiled as its solid nitrate salt.
The nitrate salt may also be used in Williamsor.
Synthesis, provided that an additional equivalent
of base, e.g. NaH is used.
Treatment of a solution of the alcohol 14, or
its nitrate salt, in methylene chloride containing
triethylamine with p-toluenesulfonyl chloride provides
tosylate 5 in good yield. The tosylate is a viscous
oil and is usually used shortly after preparation.
If desired the tosylate can be purified by filtration
through alumina with methylene chloride, but the
crude material is satisfactory. The tosylate should
be stored in the refrigerator.
Alcohol 14 may be activated by other reactants.
For example, it may be mesylated with methanesulfonyl
chloride or perhaps chlorinated with thionyl chloride
to provide additional alcohol 14 derivatives for
Williamson Synthesis.
Sodium thiolate 20 (see Scheme III) has been
alkylated with either chloro- or bromoethanol (29, Z=Cl
or Br) to afford alcohol 17. Alcohol 17 is then
converted to its corresponding tosylate 8 as shown in
Scheme VI.
~ 15~857
-16-
Scheme VI
t ~ ~ CH3~:02Cl ¢
\ e ~ \ CH cl2, TEA
~H2CHS~7a + 2c~H2c~2(~ ~I2CHSCH2~20H ~ cl'2cl~;CH2cH25~3
29 ~ ~ 8
R4~5~6 R4~5~6 R4~5r6
Tosylate 8 is also a viscous oil and is used
without rigorous purification. Alcohol 17 can be
purified by chromatography on silicic acid, or can
be isolated and purified as its hydrogen fumarate
salt.
A great number of phenols, thiophenols, benzyl
alcohols, benzyl mercaptans and benzyl halides with
which to practice this invention, are available
from commercial sources, or are known in the literature
and are readily synthesized.
For example, p-trifluoromethylthiobenzyl chloride
31 and the benzyl alcohol 30 ~ may be prepared as
follows:
/==\ BH3-~7F C ~~~ SOC12 A
2 ~ SCF3 ~ 3 ~ 2~IDMF, CH2C12~ 3 ~ ~2
29a 30 3l
'
1 1S5857
Both the alcohol 30 and the chloride 31 are suitable
substrates for Williamson Synthesis. Numerous benzoic
acids or benzoate esters are available for such re-
actions.
Operative alkylating agents may be prepared as
shown below. These agents are used to alkylate 20 (see
Scheme III).
fl ~Cl
-OH 1. NaH, diglyme ~ ~ CH2CH2Cl
2. TsOCH2CH2Cl
Cl llQ Cl 33
32
Cl f l
~ 1. NaH, DMF ~
Cl~ ------OH ~ Cl ~ \ / ~ OCH2CH2Cl
~ 2. TsOCH2CH2Cl
34 35
,~1
1. NaOEt, EtOH
34 2. Br(CEI2)3Cl ~~ Cl ~ O(CH2)3
reflux 36
~ 1~ MaOEt, E~tOH ~r~~
C1-~ -SH ) 1 - / \ ~ S
2. BrC~12C~12CH2Cl C ~ (CH2)3c
reflux 38
J
1 ~SS857
-18-
Thiophenols are also readily synthesized as
illustrated by the synthesis of the following known
compounds 40 and 42 which are utilized in preparing
the subject antimicrobials.
Cl Çl
~ /
~ ~ 1. NaNO2, HCl
Cl ( ~--NH
2- KSIC~c2~5 C1 ~ S~
39 40
3. NaOH
r 1 Mg, THF \ ~ 1H
41
From the foregoing description, it will be
understood that in general, the compounds of formula
4 may be prepared, for example, by either:
Scheme VII reacting a compound of the formula:
r
~'~
43
CH ~
~ ~ R4~5~6 with an equimolar
, ~
am~unt ~ mpound ~ ~he .~oxmula: ~1,2,3
4,4 ~ ~CH~,) n Y ~CF~) m
1 155857
--lg--
wherein Wl is either
(a) XM, M being hydrogen or an alkali metal such as
Na, K, or Li, or
(b) a leaving group such as Cl, Br,
OS2P 2tolyl or 0S02CH3, and
W is the other of (a) or (b) or
Scheme VIII reacting a compound of the formula:
N
N
_ CH21HX(CH2)nW3
~R4~5~6
~ with an equimolar amount
of a compound of the formula:
~ ,3
46 W (CH2)m -
wherein W3 is either
(c) YM, M being as defined in Scheme VII or
(d) a leaving group as defined in Scheme VII, and W4
is the other of (c) or (d),
X, Y, m, n, and Rl 6 being as defined in formula 4.
-20- 11558S7
Table I below is only illustrative of some of
the compounds of formula 4 which have been prepared.
~able_I
General_ Formula
R
N~ ~/
~1 R-ll \Rl
'rABLE I
Cpd. Acid* Addition , ._ _ __ __
No . Salt . ~ R ~ R9 Rl R-
l 4 44 -SCH2S- H H Cl H H
2 C4H404 H2CH2S H H Cl H H
3 Hh~03 -SCH2C~2S-Cl H Cl H H
4 C4H404 H2CX2S H H C6H5 H H
C4H404 -scH2cH2cH2s- H H Cl H E~
6 HNC3 -OCH2CH20- H CF3 EI H H
7 HN03 2CH20 Cl H Cl H H
8 HN03 2CH20 Cl H H H Cl
9 HN03 -OCH2CH20- Cl H Cl Cl H
C2H24 -OCH2CH20- H H tert- H H
ll C2H24 -OCH2CH20- H H C6 5 H H
12 C2H24 -OCH2CH20- Cl H C6H5 H H
13 2 24 -OCH2CH20- -C6H5 H H E H
L4 C2H24 -OCH2CH20- -C6H5 H Cl H H
L5 C2H24 -CH2cx2-- H H -CH2C6H5 E~ H
. L6 C2H24 -OC~2CH20- H H -52C6H5 H E~
1 155857
-21-
TABLE I (Cont'd.)
_ . . . . _ _
Cpd. Acid* Addition
No. Salt A R7 R8 R9 R10
. . . _ _ . _
1l
17 C2H24 -OCH2CH20- H H -CC6H5 H H
18 C4H404 2 H2 H H H H H
19 C4H404 2 2 Cl H H H Cl
C4H404 -SCH2CH2CH20- Cl H Cl H H
21 C2H24 -OCH2CH2S- H H F H H
22 HN03 -OCH2CH2S- H H Cl H H
23 HN03 -OCH2CH2S- Cl H Cl H H
24 C2H24 -OCH2CH2S- Cl H Cl Cl H
C2H24 -OCH2CH2S- H H -C6H5 H H
26 C2H24 -OCH2CH2SCH2- H H Cl H H
27 C2H24 -OCH2CH2SCH2- Cl H Cl H H
28 HN03 -OCH2CH2SCH2- H H CH3 H H
29 C2H24 -OCH2CH20CH2- H H Cl H H
C2H24 -OCH2CH20CH2- Cl H Cl H H
31 free base -OCH2CH20CH2- H H SCF3 H H
32 C2H24 -OCH2CH20CH2- H H OCH3 H H
33 C4H404 -SCH2S- Cl H Cl H H
34 C2H24 -OCH2CH20- H H -NHC6H5 H H
1l
35 free base -OCH2CH20- H H N~_JN-CCH3 H H
36 HN03 -OCH2CH2SCH2- H H OCH3 H H
37 HN03 -OCH2CH20CH2- H H C6H5 H H
38 HN03 -OCH2CH20- H H Cl **~
~/
39 C4H404 -SCH2S- Cl H H H Cl
O C4H404 -OCH2S- H H Cl H H
1 1-5 C4H404 -SCH20- H H Cl H H
2 C4H404 -SCH2SCH2- H H Cl H H
43 C2H24 -OCH~scH2- H H Cl H
* C4H404 = fumaric acid, C2H204 = oxalic acid
** R10 and Rll together form with the benzene moiety a
naphthalene ring.
1 15S857
-22-
The antifungal act~ity of compounds of general
structure A Were determined using a broth dilution
technique, against several strains of the ollowing
human and an~mal pathogenic fungi: Candida albicans,
Candida tropIcalis, Candida krusei, Trichophyton rubrum,
Trichophyton mentagrophytes and Microsporum canis.
Two-fold serial dilutions are made with Sabouraud's
liquid medium from stock solutions of the test compounds,
usually in dimethyl sulfoxide, N,N-dimethylformamide
or water. The Minimum Inhibitory Concentrations ~MIC's),
which are considered to be the minimum concentrations
of the test compounds in micrograms per milliliter
which prevent grossly detectable growth of the test
organisms, are then determined after inoculation of
the medicated broths with the test organisms, and
incubation at the appropriate temperature and for
the appropriate time interval.
Candida species are incubated for 24 hours at 37,
and five days at 28 for the dermatophytes Trichophyton
rubrum, Trichophyton mentagrophytes and Microsporum
canis.
The available antifungal MIC's of Compounds 1-32
in Table I are tabulated in Table II.
-23- 1 1SS857
_ _ _
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,~ ~ oo_ _oa~_ oo-~-o
UO~ ~ ~ ' ~
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S cn O o o r _ o ~o _ o o _ ~ ~o o o o c~, o
_ _ _
V o
c ~ ~ o c~
~ _ _ ooo C~OO~_O oo_~ocoe~J_o
1~ E 1- c~
_E ~ c~
_ _ ~ ~_ o o o o _ _
~ ~ _ _ _ ...... _. .
o~ .r
_ N
C~
~'~ o _ o c~ o ~ _ ~ o o ~ o o o o
_ ~
_ C~
U O
~ ~n _ _ _ "~ s .
el . o ooc~ o_o_~_oo~r o
C _ U~ ~ '
C ~7 O C~ O ~ _ _ O' O O ~
10 O U'>' ' U~ C:
5 ~ ~ ~~ N C`.l C~J ~11
~ a- o c~ _ o' ~ ~ _ ~- _ o _ ~ _ o o ~ ~t _ _ ~ o ~
_ V~ _ _
Z
C _ N ~ 0 ~ 0 1~ CO C O -- C~l
E _ _ _ _ _ _ _ _ _ _ ~ ~ c~
_ ~
1 155857
--2~--
-I ~
_ _ _ ~
~ ~ o ~
~ ~'~
~, I *~
~ ~o - ~ _ o ~ o ~
_ *~
,~ O ~
_ _ ~ ~oo_ ~r
~ e' ~
~ o~ ~ ~ r o o -- o ~ ~o
_ ~, _
_ ~ ~ O~q~
~ 1558~7
-~5-
The antibacterial activity of compounds of
general structure 4 has also been established. Table
III lists the antibacterial activity in MIC's of
some of the compounds described in Table I against
gram-position organisms.
Table III
_ MIC (~g/m] )a
Steptococcus Staphylococcus aureus
Cpd pneumoniae pyogenes faecalis
No.A9585* A9604* A20688* A9537* A9606* A15097*
7 63 63 2 2 2 2
8 63 63 4 2 2 2
9 63 63 2 1 1
11 125 125 8 8 8 8
18 125 125 32 16 16 16
125 125 2 1 1 2
21 63 63 2 2 2 2
22 125 125 2 2 2
24 125 125 4 1 2 2
26 ~125 ~125 2 2 2 2
29 >125 )125 4 2 2 2
63 63 1 1 1
31 >125 >125 ~ 4 4 4
*Strain number.
a. S. pneumoniae and S. pYogenes were tested
in 50% Mueller-Hinton Broth + 45% antibiotic assay
broth + 5% human serum, whereas S. faecalis and
S aureaus were tested by the agar dilution test
in Mueller-Hinton medium.
1~558~7
-26-
The following examples are only illustrative
of certain preferred embodiments of the intermediates
and antimicrobial compounds of this invention, the
structures of which as disclosed herein are supported
by satisfactory infrared and proton magnetic
resonance spectra. As employed herein and in the
appended claims, all amounts and proportions are by
weight unless otherwise indicated, temperatures are
in C, and melting and boiling points are uncorrected.
Example 1
Ethyl 2-[1-t2,4-dichlorophenyl)-2-(lH-l-imidazolyl)
ethoxy]acetate (Scheme V, ~, R4'''5=2',4-dichloro). A
solution of l-(2,4-dichlorophenyl)-2-(lH-l-imidazolyl)
ethanol* (3.0 g, 0.0118 mole) in N,N-dimethylformamide
(DMF, 7 ml) was added to a stirred, cooled (ice-water)
mineral oil suspension of 57% sodium hydride (0.55 g,
0.013 mole) in tetrahydrofuran (THF, 15 ml). The
mixture was refluxed for 1.25 hours to complete salt
formation. The cooling bath was replaced and a
solution of ethyl bromoacetate (1.5 ml, 0.014 mole)
in THF (5 ml) was added dropwise during ten minutes.
The mixture was refluxed for eighteen hours, cooled
and diluted with diethyl ether. The ethereal solution
was washed with water (3x) followed by brine and dried
(Na2SO4). After removal of the ether, the residue
was dissolved in acetonitrile and the mineral oil
removed with two n-pentane washes. Removal of the
acetonitrile left 2.55 g of the desired ester as a
clear oil, which is suitable for reduction.
*U.S. 3,717,655 and Godefrei et al, supra
1155857
-27-
~ddition of O.S ml of 70~ nitric acid (d-1.42) to
a solution of the ester (2.55 g) in diethyl ether
(50 ml) containing ethanol (10 ml) af~orded colorless
crystals (2.1 g) of the nitrate salt, mp 82-87.
Recrystallization ~rom eth~l acetate provided the
analytical sample,' mp 102-104.
- Anal- Calc'd for C15H16C12N23 HNO3
H, 4.22; Cl, 17.45; N, 10.34.
Found: C, 44.38; H, 4.15; Cl, 17.12; N, 10.72.
Example 2
1-[2-(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)-
ethyl]--lH-imidazole nitrate ~ cheme V, _, R4'5 -
2,4-dichloro). A solution of ethyl 2-[1-(2,4-
dichlorophenyl)-2-(lH-l-imidazolyl)ethoxylacetate
(6.4 g, 0.019 mole) in diethyl ether (100 ml)
was rapidly added dropwise to a cooled (ice-water),
stirred mixture of lithium aluminum hydride (0.76 g,
0.02 mole) in diethyl ether ~150 ml). The mixture
was refluxed for sixteen hours, cooled (ice-water)
and the excess hydride and aluminum complexes
decomposed by the successive dropwise additions
of water (5 ml) in THF (50 ml), 15% aqueous
sodium hydroxide (10 ml) and water (5 ml). The
mixture was stirred for an additional thirty
minutes and filtered into a separatory funnel.
The aqueous layer was extracted with diethyl
ether (3x) and the combined ethereal layers
washed with water, followed by brine (2x~. After
drying (Na2SO4) and removal of the ether there
remained 5.12 g of the desired alcohol as a viscous
oil.
1 15S857
-28-
Treatment of an ethereal solution o~ the free
base with 70% nitric acid afforded the nitrate salt
which melted at 97.5-98.5 after recr~stallization
from acetonitrile-ether.
Anal. Calc'd for C13H14C12N2O2 3
Cl, 19.47; N, 11.54.
Found: C, 43.02; H, 4.13; Cl, 19.29; N, 11.57.
Example 3
Tosylate of 1-[2-(2,4`-dichlorophenyl)-2-(2-hy4droxy-
ethoxy)ethyl]-lH-imidazole (Schemes I and V, 5, R '5 =
2,4-dichloro). The nitrate salt of 1-~2-(2,4-
dichlorophenyl)-2-(2-hydroxyethoxy)ethyl]-lH-
imidazole (6.0 g) was Partitioned between methylene
chloride (CH2C12) and 0.5 N NaOH (40 ml). The CH2C12
layer was washed (brine) and dried (Na2SO4). Removal
of the CH2C12 left the free base (5.02 g), of the
alcohol. p-Toluenesulfonyl chloride (3.50 g, 0.0184
mole) was added to a cooled (ice-water), stirred
solution of the alcohol (5.02 g, 0.0167 mole) in
CH2C12 (60 ml) containing triethylamine (2.56 ml,
0.0167 mole). Stirring was continued at ice-bath
temperature (one hour) and then at 25 (one hour).
The mixture was successively washed with cold water,
cold aqueous Na2CO3 (2x), water and brine. The CH2C12
solution was dried (Na2SO4) and concentrated to dryness
to afford 7.15 g of the tosylate as a viscous oil.
If desired, a solution of the tosylate in CH2C12 can be
filtered through alumina to remove traces of starting
alcohol. The latter operation is, however, not necessary
for subsequent reactions.
1 15S8S7
-29-
The nitrate salt of 1-~2-(2,4-dichlorophenyl)-2-(2-
hydroxyethoxy)ethyl]-lH-imidazole may be directly
utilized in tosylate formation provided that an ad-
ditional e~uivalent of triethylamine is added.
Example 4
1-[2-(4-biphenylyloxyethox~)-2-(2,4-dichlorophenyl)
ethyl]-lH-imidazole hydrogen oxalate (Table I, Compound
No. 11). A solution of 4-hydroxybiphenyl (2.42 g,
O.0142 mole) in DMF (15 ml) was added dropwise to a
cooled (ice-water) stirred, mineral oil suspension of
57% NaH (0.658 g, 0.0156 mole) in DMF (25 ml). Stirring
was continued at 70 (20 minutes) and then at 100 (10
minutes) to complete salt formation. The cooling bath
was replaced and a solution of the tosylate of 1-[2-
(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)ethyl]-lH-
imidazole (6.47 g, 0.0142 mole) in THF (15 ml) added.
The mixture was stirred for eighteen hours at an oil
bath temperature of 75 under nitrogen and concentrated
to dryness. The residue was partitioned between diethyl
ether and water. The ethereal layer was washed with
water (2x), followed by brine and dried (Na2SO4). After
removal of the ether the residue was dissolved in ace-
tonitrile and the mineral oil removed with two n-pentane
washes. Removal of the acetonitrile left the crude free
base (5.2 g), as a viscous oil which afforded 4.2 g, of
pure base after chromatography on silicic acid (150 g)
with methylene chloride-acetone (10:1).
A solution of the free base (4.0 g, 0.00882 mole)
in ethyl acetate tlO0 ml) was treated with a solution of
oxalic acid (0.794 g, 0.00882 mole) in ethyl acetate (S0
ml) to provide, upon cooling, 4.28 g of the hydrogen
oxalate salt, mp 122-124 (decomp.).
1 155857
-30-
Anal. Calc'd for C25H22cl2o2N2 c2 2 4
H, 4.45; Cl, 13.04; N, 5.16.
Found: C, 59.39; H, 4.51; Cl, 13.24; N, 5.16.
Replacement of the 4-hydroxybiphenyl in the above
procedure with 4-chloro-2-phenylphenol, 2-chloro-4-
phenylphenol, 2-phenylphenol, 4-benzylphenol, 2,6-
dichlorophenol, 4-fluorothiophenol, 4-mercaptobiphenyl,
4-chlorobenzyl mercaptan, and 4-methylbenzyl mercaptan
and use of the suitable salt-forming acid,; gave the
following crystalline acid addition salts, respectively:
1-[2-(4-chloro-2-phenylphenoxyethoxy)-2-(2,4-
dichlorophenyl)ethyl]-lH-imidazole hydrogen oxalate,
mp 88-91 (Table I, Compound No. 14).
Anal. Calcld for C25H21C13N2O2-C2 2 4
H, 4.01; N, 4.85.
Found: C, 56.24; H, 4.19; N, 5.01.
1-[2-(2-chloro-4-phenylphenoxyethoxy)-2-(2,4-dichloro-
phenyl)ethyl]-lH-imidazole hydrogen oxalate, mp 93-95
(Table I, Compound No. 12).
-
Anal. Calc'd for C25H21C13N2O2-C2 2 4
C, 56.12; H, 4.01; N, 4.85.
Found: C, 56.00; H, 4.15; N, 5.16.
1-[2-(2,4-dichlorophenyl)-2-(2-phenylphenoxyethoxy)ethyl]-
lH-imidazole hydrogen oxalate, mp 140-141 (Table I !_
Compound No. 13).
Anal. Calc'd for C25H22C12N2O2.C2H2o4:
C, 59.68; H, 4.45; Cl, 13.05; N, 5.16.
Found: C, 59.28; H, 4.55; Cl, 12.86; N, 5.27.
1-[2-(4-benzylphenoxyethoxy)-2-(2,4-dichlorophenyl)ethyl]-
lH-imidazole hydrogen oxalate, mp 117-118 (Table I,
Compound No. 15).
-`` ' 11S58S7
-31-
Anal. Calc'd for C26H24C12N22 1 ( 2 2 4
C, 57.82; H, 4.52~ Cl, 11.77; N, 4.65.
Found: C, 57.58; H, 4.62; Cl, 11.43; N, 4.56.
1-~2-(2,6-dichlorophenoxyethoxy)-2-(2,4-dichlorophenyl)-
ethyl]-lH-imidazole nitrate, mp 106-108 (Table I, Compound
No. 8).
Anal. Calc'd for ClgH16C14N2O2 3
C, 44.82; H, 3.37; Cl, 27.85; N, 8.25.
Found: C, 44.84; H, 3.38; Cl, 27.47; N, 8.28.
1-12-(2,4-dichlorophenyl)-2-(4-fluorothiophenoxyethoxy)-
ethyl]-lH-imidazole hydrogen oxalate, mp 107-108 (Table I,
Compound No. 21).
Anal. Calc'd for ClgH17C12FN2OS.C2H2O4:
C, 50.31; H, 3.82; Cl, 14.14; N, 5.59; S, 6.40
Found: C, 50.38; H, 3.93; Cl, 14.01; N, 5.78;
S, 6.88
1-(2-[2,4-dichlorophenyl]-2-[(4-biphenylthio)ethoxy]ethyl)-
lH-imidazolehydrogen oxalate (Table I, Compound No. 25).
nal. C lc d for C25H20C12N2S C2H24
C, 57.96; H, 4.32; N, 5.01; S, 5.73.
Found: C, 57.68; H, 4.35; N, 5.15; S, 5.25
1-(2-[(4-chlorobenzylthio)ethoxy]-2-[2,4-dichlorophenyl]
ethyl)-lH-imidazole hydrogen oxalate, mp 98-100 (Table I,
Compound No. 26).
2g Anal- Calc'd for C20Hl9Cl N2S C2H24-
C, 49.68; H, 3.98; Cl, 20.00; N, 5.27; S, 6.03.
Found: C, 49.94; H, 3.95; Cl, 19.81; N, 5.38;
S, 6.37.
1-(2-[2,4dichlorophenyl]-2-[(4-methylbenzylthio)ethoxy]-
ethyl)-lH-imidazole nitrate, mp 107-108 (Table I, Compound
No. 28).
Anal- Calc'd for C21H22C12N2S-HN3
C, 52.07; H, 4.79; Cl, 14.64; N, 8.67; S, 6.62.
Found: C, 51.85; H, 4.68; Cl, 14.71; N, 8.64;
S, 6.49~
115$857
-32-
Example 5
1-[2-(2~4-dichlorophenyl~-2-(2,4,5-trichloro-
phenoxyethoxy)ethyl]-lH-imidazole nitrate (Table I,
Compound No. 9). A solution of 2,4,5-trichlorophenol
(3.41 g, 0.0173 mole) in DMF (10 ml) was added
dropwise during five minutes to a ~tirred, cooled
(ice-water) mixture of 57% sodium hydride in mineral
oil (0.727 g, 0.0173 mole) in DMF (25 ml). Stirring
was continued at 50-120 for 0.5 hour to complete
salt formation. The ice-bath was replaced and a
solution of the tosylate of l-[2-(2,4-dichlorophenyl)-
2-(2-hydroxyethoxy)ethyl]-lH-imidazole (7.15 g,
0.0157 mole) in THF (25 ml) added dropwise during
five minutes. The mixture was heated under gentle
reflux for eighteen hours and concentrated to dryness.
The residue was partitioned between diethyl ether
and water. The ethereal layer was washed (water,
brine) and dried (Na2SO4). After removal of the
ether the residue was dissolved in acetonitrile and
the solution washed with n-pentane (2x) to remove
the mineral oil. Removal of the acetonitrile left a
gum (6.23 g) which was dissolved in a mixture of
diethyl ether (100 ml) and ethyl acetate (25 ml).
Addition of 70% nitric acid (d=1.42) caused the
titled nitrate salt to separate, mp 100-110. Two
recrystallizations from ethyl acetate, the latter
with the addition of decolorizing carbon, provided
beige crystals of the analytical sample, mp 143-
144.5.
Anal- Calc'd for Cl9H15C15N22 HN3
C, 41.98; H, 2.97; N, 7.73.
Found: C, 42.27; H, 3.06; N, 7.64.
By proceeding in a similar manner and replacing
the 2,4,5-trichlorophenol with 4-tert-butylphenol, 4-
phenylsulfonylphenol*, 4-hydroxybenzophenone, 2,4,5-
trichlorothiophenol, and 4-methoxybenzyl alcohol, the
following compounds were prepared, and characterized
*Szmant und Suld, J. Amer. Chem. Soc., 78, 3400 (1956).
1 155857
-33-
as hydrogen oxalate salts, respectively:
1-[2-(4-tert-butylphenoxyethoxy)-2-(2,4-dichlorophenyl)
ethyl]-lH-imidazole, mp 141-143 (decomp) (Table I,
Compound No. 10).
Anal. Calc'd for C H Cl N O .C H O :
--- 23 26 2 2 2 2 2 4
C, 57.37; H, 5.39; Cl, 13.55; N, 5.35.
Found: C, 56.71; H, 5.06; Cl, 13.47; N, 5.06
1-[2-(2,4-dichlorophenyl)-2-(4-phenylsulfonylphenoxyethoxy)-
ethyl]-lH-imidazole, mp 169-171 (decomp) (Table I,
Compound No. 16).
Anal- Calc'd for C25H22C12N24S C2H24
C, 53,39; H, 3.98; Cl, 11.67; N, 4.61; S, 5.28.
Found: C, 53.39; H, 3.98; Cl, 11.70; N, 4.83;
S, 5.42.
1-~2-(4-benzoylphenoxyethoxy)-2-(2,4-dichlorophenyl)-
ethyl]-lH-imidazole, mp 118-124 (Table I, Compound
No. 17).
Anal. Calc'd for C26H22C12N2O3.C2H2O4:
C, 57.72; H, 4.37; Cl, 12.19; N, 4.89.
Found: C, 58.09; H, 4.46; Cl, 12.41; N, 4.85.
1-[2-(2,4-dichlorophenyl)-2-(2,4,5-trichlorothiophenoxy-
ethoxy)ethyl]-lH-imidazole, mp 108.5-109.5 (Table I,
Compound No. 24).
Anal- Calc d for Cl9H15C15N2S C2H24
C, 42.99; H, 2.92; Cl, 30.31; N, 4.77; S, 5.47.
Found: C, 42.90; H, 2.78; Cl, 30.08; N, 5.10;
S, 5.30.
1-[2-(2,4-dichlorophenyl)-2-(4-methoxybenzyloxyethoxy)-
ethyl]-lH-imidazole, mp 155.5-157.5 (Table I, Compound
No. 32).
Anal. Calc'd for C21H22C12N2O3.C2H2O4:
C, 54.02; H, 4.73; Cl, 13.87; N, 5.48.
Found: C, 53.90; H, 4.78; Cl, 13.82; N, 5.77.
Example 6
1-[2-(4-chlorothiophenoxyet oxy)-2-(2,4-dichloro-
1 155857
-34-
phenyl)ethyl]-lH-imidazole nitrate (Table I, Compound
No. 22). 50~ Sodium hydride dispersion in mineral
oil (0.21 g, 4.4 mmoles) was added to a stirred
solution of 4-chlorothiophenol (0.64 g, 4.4 mmoles)
S in DMF ~25 ml) at 20. Stirring was continued at
ambient temperature for 1.5 hours and then at 50-60
for 0.5 hour. The solution was cooled to 20 and a
solution of the tosylate of l-[2-(2,4-dichlorophenyl)-
2-(2-hydroxyethoxy)ethyl]-lH-imidazole (2.0 g, 4.4
mmoles) in DMF ~10 ml) added. The mixture was
heated at an oil bath temperature of 75 for three
hours and concentrated to dryness. The residue was
partitioned between CH2C12 and water and the aqueous
layer extracted with CH2C12. The combined CH2C12
layers were evaporated to dryness and the residue
dissolved in acetonitrile. The mineral oil was
removed with two n-pentane washes. Removal of the
acetonitrile left 2 g of a viscous oil which afforded
0.87 g of the pure base, after chromatography on
neutral alumina (50 g) with CH2C12. A solution of
the free base (0.87 g) in diethyl ether (100 ml) was
converted to the nitrate salt by adding 70% nitric
acid (d=1.42) until precipitation was complete.
Recrystallization from acetonitrile ether provided
an analytical sample of the title compound, mp 98-
990
Anal- Calc'd for Cl9H17C13N2S-HN3
C, 46.49; H, 3.70; Cl, 21.67; N, 8.56; S, 6.53.
Found: C, 46.76; H, 3.65; Cl, 21.58; N, 8.42;
S, 6.56.
By proceeding in a similar manner and replacing the
4-chlorothiophenol with 2,4-dichlorothiophenol, 2,4-di-
chlorophenol and 3-trifluoromethylphenol, the followin~-
compounds were prepared and characterized as nitrate
salts:
1-[2-(2,4-dichlorophenyl)-2-(2,4-dichlothiorophenoxy-
ethoxy)ethyl]-lH-imidazole, mp 172-173 (Table I,
Compound No. 23).
1 1S5857
-35-
ClgH16Cl4N2Os-HNO3
C, 43.44; H, 3.26; N, 8.00; S, 6.10.
Found: C, 43.75; H, 3.24; N, 8.14; S, 6.00.
1-[2-(2,4-dichlorophenoxyethoxy)-2-(2,4-dichlorophenyl)-
ethyl-lH-imidazole, mp 173.5-174.5 (Table I,
Compound No. 7).
ClgH16Cl4N2O2-HNO3
C, 44.81; H, 3.17; N, 8.25.
Found: C, 44.86; H, 3.36; N, 8.47.
1-[2-(2,4-dichlorophenyl)-2-(3-trifluoromethylphenoxy-
ethoxy)ethyl]-lH-imidazole, mp 105.5-107.5 (Table I,
Compound No. 6).
Anal. Calc'd for C20Hl7C12F3N2 2 3
C, 47.26; H, 3.57; N, 8.27.
Found: C, 46.98; H, 3.48; N, 8.53.
Example 7
1-(2-[(2,4-dichlorobenzylthio)ethoxy]-2-[2,4-
dichlorophenyl]ethyl)-lH-imidazole hydrogen oxalate
(Table I, Compound No. 27). A 1.6 M solution of n-
butyl lithium in hexane (6.3 ml, 0.01 mole) was
added dropwise to a stirred solution of 2,4-dichloro-
benzyl mercaptan (1.93 g, 0.01 mole) in THF (65 ml)
at -78. Stirring was continued at -78 for 0.5 hour
and a solution of the tosylate of l-[2-(2,4-dichloro-
phenyl)-2-(2-hydroxyethoxy)ethyl]-lH-imidazole (4.55
g, 0.01 mole) in THF (35 ml) added dropwise. The
mixture was stirred an additional 0.5 hour at -78
and then for 1.5 hours at ambient temperature. The
~olvents were removed in vacuo and a mixture of the
residue in water extracted with CH2C~2 (3x). The
combined CH2C12 extracts were washed with brine
(3x), then water and dried (Na2SO4). Removal of the
~ 1 155857
-36-
solvent, after treatment with decolorizing carbon,
afforded 4.~ g of oil which gave 2.99 g of pure free
base after chromatography on 9ilicic acid (100 g)
with CH2C12acetone ~20:1). Addition of oxalic acid
to a solution of the free base in ethyl acetate gave
the titled salt (2.77 g), mp 85-88.
1. C lc d for C20H18C14N2OS.C2H2O4:
C, 46.66; H, 3.56; N, 4.95.
Found: C, 46.49; H, 3.55; N, 5.17.
Example 8
1-[2-(4-chlorobenzyloxyethoxy?-2-(2,4-dichloro-
phenyl)ethyl]-lH-imidazole hydro~en oxalate
(Table I, Compound No. 29). A solution of 1-[2-
(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)ethyl]-lH-
imidazole nitrate (2.5 g, 6.87 mmoles) in DMF (15 ml)
was added dropwise during fifteen minutes to a
stirred, cooled (ice-water) mineral oil suspension
of 57% sodium hydride (0.61 g, 14.4 mmoles) in a
mixture of`DMF (10 ml) and THF (10 ml) under nitrogen.
Stirring was then continued for 0.5 hour at 25 and
for 0.25 hour at 50. The cooling bath was replaced
and the 4-chlorobenzyl chloride (1.22 g, 7.56 mmoles)
radidly added. The mixture was stirred at ambient
temperature for 35 minutes and then at an oil
bath temperature of 65 for 1.5 hours. The mixture
was concentrated to dryness and the residue partitioned
between diethyl ether and water. The athereal layer
was washed (water, brine), dried (Na2SO4) and concentrated
to dryness. The residue was dissolved in acetonitrile
and the mineral oil ramoved by washing with n-pentane
(3x). The residue (2.35 g) was chromatographed on
alumina (130 g) with CH2C12-ethanol (25:1) to give
the pure free base (1.26 g) as a yellow oil. Treatment
1 155857
-37-
of a solution of the free base (1.2 g) in ethyl acetate
with oxalic acid ~0.254 g) afforded the title compound,
mp 103-105.
Anal. Calc'd for C~oHlgC13N202~C2H404
C, 51.23; H, 4.10; Cl, 20.62; N, 5.43.
Found: C, 51.35: H, 4.02; Cl, 20.60; N, 5.68.
In a similar manner, replacing the 4-chlorobenzyl
chloride with 2,4-dichlorobenzyl chloride and 4-tri-
fluoromethylthio benzyl chloride provided, respectively:
1-~2-(2,4-dichlorobenzyloxyethoxy)-2-(2,4-dichlorophenyl)-
ethyl]-lH-imidazole hydrogen oxalate, mp 100-103
tTable I, Compound No. 30).
Anal- Calc'd for C20H18C14N22 C2 2 4
C, 48.02; H, 3.66, Cl, 25.77; N, 5.09.
Found: C, 48.10; H, 3.65; Cl, 25.66;
N, 5.34.
1-[2-(2,4-dichlorophenyl)-2-t4-trifluoromethylthio-
benzyloxyethoxy)ethyl]-lH-imidazole, mp 51-52 tTable I,
Compound No. 31).
Anal. Calc'd for C21HlgC12F3N2O2S:
C, 51.33; H, 3.90; Cl, 14.43; N, 5.70.
Found: C, 51.60; H, 3.75; Cl, 14.38; N, 5.80.
Example 9
4-trifluoromethylthiobenzyl alcohol t30). A 1.02
M solution of borane in THF t56.9 ml, 0.058 mole) was
added dropwise during 0.25 hour to a stirred solution
of 4-carboxyphenyl trifluoromethyl sulfide (10.0 g,
0.045 mole) in THF (25 ml) at -5. The cooling bath
was removed and stirring continued for three hours at
25. The cooling bath was replaced and 30 ml of
water -THF (1:1) cautiously added. The aqueous phase
1 155857
-38-
was saturated with potassium carbonate and the layers
separated. The aqueous phase was extracted with
diethyl ether (4 x 25 ml). The ethereal extracts were
combined with the THF layer and the combination washed
(water) and dried (Na2SO4). Removal of the solvents
left an oil which crystallized when triturated with
6 N HCl. Recrystallization from Skellysolve-B
provided the alcohol (6.5 g), mp 52-53.
Anal. Calc'd for C8H7F3OS: C, 46.15; H, 3.39.
Found: C, 46.44; H, 3.51.
Example 10
4-trifluoromethylthiobenzy-l-chloride (31). Thionyl
chloride (2.48 g, 0.0208 mole) was added dropwise to a
stirred solution of 4-trifluoromethylthiobenzyl alcohol
(4.0 g, 0.0192 mole) in CH2Cl (40 ml) at 5. One drop
of DMF was then added and the solution stirred for
eighteen hours at 25. The solution was concentrated
and the residue triturated with ice-water and extracted
with CH2C12. The CH2C12 solution was washed (water)
and dried (Na2SO4). Removal of the solvent left 4.0 g
of the titled product as a mobile oil.
Anal. Calc'd for C8H6ClF3S: C, 42.39; H, 2.67; Cll 15.65.
Found: C, 42.31; H, 2.76; Cl, 15.26.
Example 11
.
1-[2-(2,4-dichlorophenyl)-2-(2-hydroxyethyLthio)ethyl]-
et4hyl]-lH-imidazo~e hydrogen fumarate (Schemes II and VI, 17,
R ' = 2,3-dichloro). To a stirred solution of sodium hydrox-
ide (5.8 g, 0.145 mole) in ethanol (650 ml) at 25 under a
blanket of nitrogen, was added 1-[2-(2,4-dichlorophenyl)-
2-(ethoxythiocarbonylthio)ethyl]-lH-imidazole hydrogen
1 15S857
~39
oxalate* (13.1 g, 0.029 mole?. After stirring for an
additi~onal 0.75 hour at 25 a solution of 2-bromoethanol
(3.87 g, 0.031 mole) ln ethanol ~10 ml) was added.
Stirring was continued for one hour and the ethanol
removed. The residue was partitioned between diethyl
ether and water. The aqueous layer was extracted with
several portions of ether and the combined ethereal
layers washed with water followed by brine. Removal
of the ether, after drying with Na2SO4, left 9.3 g of
the free base as a viscous oil. Addition of fumaric
acid (3.40 g~ to a solution of the free base (9.3 g) in
l-propanol (30 ml~ provided, after removal of the 1-
propanol and two recrystallizations from acetonitrile,
colorless crystals (8.8 g) of the titled salt, mp 124-
125 (foamingl.Anal- Calc'd fr C13H14C12N2~S-C4H404
C, 47.12; H, 4.19; Cl, 16.37; N, 6.47; S, 7.40.
Found: C, 47.07; H, 4.00; Cl, 16.31; N, 6.80;
S, 7.40.
A similar procedure using 2-chloroethanol in place
of the 2-bromoethanol provided the free base as a
viscous oil after chromatography on silicic acid with
chloroform-acetone tl:l).
Example 12
1-[2-(4-chlorothiophenoxyethylthio)-2-(2,4-di-
chLorophenyl)ethyl]-lH-imidazole hydrogen fumarate (Table I,
Compound No. 2). p-Toluenesulfonyl chloride t930 mg.,
4.9 mmoles) was added to a cooled (ice-water), stirred
solution of l-[2-(2,4-dichlorophenyl)-2-(2-hydroxy-
ethylthio)ethyl]-lH-imidazole tl.4 g, 4.41 mmoles) in
CH2C12 (20 ml) containing triethylamine (0.61 ml,
4.41 mmoles~. Stirring was continued at ice bath
temperature ~0.75 hour~ and then at 25 ~0.75 hour).
*U.S. 4,038,409 and 4,039,677
1 155857
,
-40-
The mixtUre was then successi~ely wa8hed With the
following cold aqueous solutions: water ~2x], 2~
K2CO3-water ~2x), ~ater ~2x? and ~rine. Removal of
the solvent, after drying with Na2SO4, left 2.03 g
of the tosylate of 1-[2-~2,4-dichlorophenyl)-2-~2-
hydroxyethylthio)ethyl]-lH-imidazole as a viscous oil.
A solution of 4-chlorothiophenol (0.67 g, 4.66
mmoles) in DMF ~3 ml) was added during five minutes
to a cooled (ice-water), stirred suspension of 57%
sodium hydride in mineral oil tl96 mg, 4.66 mmoles)
in DMF (8 ml). The mixture was then heated at an oil
bath temperature of 110 for 0.5 hour. The cooling
bath was replaced and a solution of the aforesaid
tosylate (2.03 g, 4.3L mmoles) in THF (8 ml) added
during five minutes. The mixture was gently refluxed
for six hours and concentrated to dryness in vacuo.
The resulting oil was diLuted with water and the
- mixture extracted with several portions of diethyl
ether. The combined ethereal extracts were washed
(water, brine), dried tNa2SO4) and concentrated to
leave an oil which was dissolved in acetonitrile
~CH3CN). The CH3CN solution was washed with n-pentane
(2x). Removal of the CH3CN left the free base ~1.29 g)
of the title compound. A solution of the free base
25 ~1.29 g) in CH3CN was treated with fumaric acid ~0.31 g)
to provide the title compound ~0.85 g), mp 95-98
(foaming). Recrystallization from CH3CN gave colorless
crystals of the analytical sample, mp 96-98.
A~a;l. Calc'd for Cl9H17C13N2S2-C4 4 4
C, 49.33; H, 3.78; Cl, 19.00; N, 5.40; S, 11.45
Found: C, 49.47; H, 3.86; Cl, 18.72; N, 5.08;
S, 11.48.
1155857
-41-
In a similar manner, replacement of the 4-
chlorothiophenol with 2,4-d~chlorothiophenol and 4-
mercaptobiphenyl, and use of the suitable salt-forminq
acid, gave respectively:
1-[2-(2,4-dichlorothiophenoxyethylthio)-2-(2,4-di-
chlorophenyL)ethyl]-lH-imidazole nitrate, mp 104-105
(Table I, Compound No. 3).
Anal. Calc d for ClgH16C14N2S2 HN3
C, 42.15; H, 3.17; Cl, 26.20; N, 7.76.
Found: C, 42.34; H, 2.78; Cl, 25.97; N, 8.12.
1-[2-(4-biphenylylthioethylthio)-2-(2,4-dichlorophenyl)-
ethyl]-lH-imidazole hydrogen fumarate, mp 116-119
(Table I, Compound No. 4).
Anal. Calc'd for C25H22C12N2S2 C4 4 4
Cl, 11.79; N, 4.66; S, 10.66.
Found: Cl, 12.20; N, 5.00; S, 10.38.
Example 13
1-[2-(2~4-dichlorophenyl)-2-(4-chlorophenylthio-
propylthio)ethyl]-lH-imidazole hydrogen fumarate (Table
I, Compound No. S~. To a stirred solution of sodium
hydroxide (1.55 g, 0.0388 mole) in ethanol (176 ml)
at 25 under a blanket of nitrogen, was added 1-~2-
(2,4-dichlorophenyl)-2-(ethoxythiocarbonylthio)ethyl]-
lH-imidazole hydrogen oxalate* (3.5 g, 7.7 mmoles).
After stirring at 25 for 0.75 hour, 4-chlorophenyl
3-chloropropyl sulfide (1.8 g, 8.1 mmoles) was added
dropwise during five minutes. The mixture was refluxed
for eighteen hours and concentrated to dryness. The
residue was diluted with water and the mixture extracted
with several portions of diethyl ether. The combined
*As in Example 11.
-42- 1 155857
ethereal layers were washed (water) and dried tNa2SO4).
Removal of the ether left a viscous oil (3.8 g).
Fumaric acid (0.96 g) wa~ added to a hot solution
of the oil in CH3CN(10 ml). Upon cooling colorless
crystals (3.3 g) of the titled compound separated,
mp 116-117.
Anal- Calc'd for C20Hl9C13N2S2 4 4 4
C, 50.22, H, 4.04; Cl, 18.53; N, 4.88.
Found: C, 50.19; H, 4.06; Cl, 18.66; N, 5.05.
In a similar manner, replacement of the 4-chloro-
phenyl 3-chloropropyl sulfide with chloromethyl 4-
chlorophenyl sulfide, and 2,4-dichlorophenyl 3-chloro-
propyl ether gave, respectively:
1-[2-(4-chlorothiophenoxymethylthio)-2-(2,4-dichloro-
phenyl)ethyl]-lH-imidazole sesquifumarate, mp 125-126
(foaming) (Table I, Compound No. 1).
Anal. Calc'd for C H Cl N S .1.5 C H O :
18 15 3 2 2 4 4 4
C, 47.73; H, 3.51; Cl, 17.61; N, 4.64; S, 10.62.
Found: C, 47.64; H, 3.59; Cl, 17.41; N, 4.92;
S, 10.29.
1-[2-(2,4-dichlorophenoxypropylthio)-2-(2,4-dichloro-
phenyl)ethyl]-lH-imidazole hydrogen fumarate, mp 138-139.5
(Table I, Compound No. 20).
1. C lc d o C20H18 14N2OS-C4H404
C, 48.66; H, 3.74; Cl, 23.95; N, 4.73; S, 5.41.
Found: C, 49.04; H, 3.75; Cl, 23.41; N, 4.90;
S, 5.60.
Example 14
1-[2-t2,4-dichlorophenyl)-2-(phenoxyethylthio)-
ethyl]-lH-imidazole hydrogen fumarate (Table I, Compound
No. 18). 1-[2-(2,4-dichlorophenyl)-2-(ethoxythiocarbonylthio)-
ethyl]-lH-imidazole hydrogen oxalate (1.1 g, 2.45 mmoles)
1155857
-43-
was added to a stirred, cooled ~ice-water~ solution of
sodium hydroxide (0.49 g, ~.0123 mole) in methanol t6Q ml)
under nitrogen. The ice bath was removed after stirring
for 0.25 hour. Stirring was continued at 25 for 0.5
5 hour and a solution of ~-bromophenetole tO.49 g, 2.42
mmoles) in methanol (10 ml) added. The mixture was
stirred at room temperature for one hour and then
refluxed for two hours. The methanol was removed
and a mixture of the residue in water extracted with
10 two portions of diethyl ether. The combined ethereal
extracts were washed with 5% aqueous K2CO3 (3x) followed
by water. The ether layer was then extracted with
dilute hydrochloric acid and the aqueous layer washed
with several portions of ether. The aqueous layer
15 was made basic with aqueous sodium hydroxide and the
free base extracted into ether. The ethereal layer
was dried (Na2SO4) and concentrated to afford 700 mg
of a viscous oil, a portion of which (520 mg), when
chromatographed on silicic acid (20 g) with CH2C12-
20 acetone (lOO:lS) gave 260 mg of purified free base.
Treatment of a solution of the free base in acetonitrile
with fumaric acid, provided colorless crystals of the
titled salt, mp 116-117.
o ClgHlgcl2N2Os-c4H4O4
C, 54.23; H, 4.35; N, S.S0.
Found: C, 53.48; H, 4.36; N, 5.51.
In a similar manner, replacement of the ~-bromo-
phenetole with 2-chloroethyl 2,6-dichlorophenyl ether
gave 1-[2-(2,6-dichlorophenoxyethylthio~-2-(2,4-
30 d;chIorophenyl)ethyl]-lH-im~dazole hydrogen fumarate,
mp 107-108 (Table I, Compound No. 19).
A C f ClgH16C14N2OS-c4H404
C, 47.76; H, 3.49; N, 4.84.
Found: C, 47.87; H, 3.50; N, 4.81.
1 155857
-44-
Example 15
3-chloropropyl 2,4-dichlorophenyl ether* (36).
l-bromo-3-chloropropane (60 g, 0.38 mole) was
added to a solution of 2,4-dichlorophenol (40.8 g, 0.25
mole) in 0.5 M ethanolic sodium ethoxide (500 ml). The
mixture was refluxed for two hours, cooled and diluted
with water (500 ml). The mixture was extracted with
CH2C12. The CH2C12 layer was washed (aqueous NaHCO3),
concentrated and the resulting oil distilled to provide
40.5 g of the title compound, bp 114-115 (0.2 mm).
In a similar manner, treatment of l-bromo-3-
chloropropane with 4-chlorothiophenol provided 3-
chloropropyl 4-chlorophenyl sulfide** (Scheme VI, 41),
bp 107-108 (0.2 mm).
Example 16
2-_hloroethyl 2,6-dichlorophenyl ether (33).
A solution of 2,6-dichlorophenol (32.6 g, 0.20
mole) in diglyme (65 ml) was added to a cooled (ice-
water), stirred mineral oil suspension of 57~ sodium
hydride (9.3 g, 0.22 mole) in diglyme (90 ml) containing
DMF (5 ml). The mixture was stirred for five minutes
at 40 and the cooling bath replaced. A solution of
2-chloroethyl p-toluenesulfonate (47 g, 0.020 mole) in
diglyme (20 ml) was then added during twenty minutes.
The mixture was heated at an oil bath temperature of
110 for nineteen hours, and partially concentrated.
The mixture was diluted with cold water and extracted
with diethyl ether (2x 125 ml). The combined ethereal
extracts were washed successively with ice cold 1 N
*Dutch Patent 94,934 (1960)
**Bird and Stirling, J. Chem. Soc. (B), 111 (1968).
1 15585't
-45-
NaOH, water and brine. The ethereal solution was
dried (Na2SO4), concentrated and the residue distilled
to provide 35.5 g of the title compound, bp 79-81
(0.1 mm).
2-chloroethyl 2,4-dichlorophenyl ether* (3S),
bp 107-111 (0.75 mm) was similarly prepared.
Example 17
1-[2-(4-chloronaphthoxyethoxy)-2-(2,4-dichloroPhenvlj-
ethyl]-lH-imidazole nitrate (Table I, Compound No.
_
38). A solution of 4-chloro-1-naphthol (1.68 g, 9.4
mmoles) in DMF (5 ml) was rapidly added to a cooled
(ice-water), stirred, mineral oil suspension of 57%
NaH (435 mg, 10.3 moles) in DMF (15 ml). The cooling
bath was removed and stirring continued for five
minutes at 5-35 to complete salt formation. The
cooling bath was replaced and a solution of the
tosylate of 1-[2-(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)-
ethyl]-lH-imidazole (4.28 g, 9.4 mmoles) in the THF
(15 ml) added. The mixture was stirred under gentle
reflux for eighteen hours and concentrated to dryness.
The residue was partitioned between diethyl ether
and water. The ethereal layer was successively
washed with 1 N NaOH, water, brine and dried (Na2SO4).
After removal of the ether the residue was dissolved
in acetonitrile and the mineral oil removed with two
n-pentane washes. Removal of the acetonitrile left
the crude free base (3.30 g), as a viscous brown oil
which afforded 2.18 g of pure base after chromatography
on silicic acid (120 g) with methylene chloride-
acetone (10:1).
*Foldeak et al, Acta Phys. Chem. 9, 134 (1963)
-46- 1 1558s7
Addition of 0.3 ml of 70% nitric acid (d-1.42) to
a solution of the purified free base (2.18 g) in ethyl
acetate provided the nitrate Ralt, mp 88-95. ~e-
crystallization from ethyl acetate a~forded peach
crystals of the analytical sample, mp 154-156.
alc d for C23H19C13N22 HN3
C, 52.64; H, 3.84; Cl, 20.27; N, 8.01.
Found: C, 52.45; H, 3.92; Cl, 20.30; N, 7.79.
In a similar manner, replacement of the 4-chloro-1-
naphthol in the above expeximent with p-hydroxydiphenyl-
amine, 4-(4-acetyl-1-piperazinyl)phenol* and p-
methoxybenzyl mercaptan and use of the suitable salt-
forming acid, gave the following products, respectively:
1-~2-(4-anilinophenoxyethoxy)-2-(2,4-dichlorophenyl)-
ethyl]-lH-imidazole hydrogen oxalate, mp 131-135
(Table I, Compound No. 34).
Anal. Calc'd for C25H23C12N32 2 2 4
C, 58.07; H, 4.51; Cl, 12.70; N, 7.52.
Found: C, 57.71; H, 4.53; Cl, 12.45; N, 7.57.
1-(2-[4-(4-acetyl-1-piperazinyl)phenoxyethoxy]-2-[2,4-
dichlorophenyl]ethyl)-lH imidazole, mp 128-130
(Table I, Compound No. 35).
Anal. Calc'd for C25H28C12N4O3:
C, 59.65; H, 5.61; Cl, 14.08; N, 11.13.
Found: C, 59.90; H, 5.64; Cl, 13.88; N, 10.92.
1-(2-[2,4-dichlorophenyl]-2-[(4-methoxybenzylthio)ethoxy~-
ethyl)-lH-imidazole nitrate, mp 86-88 (Table I, Compound
No. 36).
*German OLS 2804096
-47_ 1 155857
Anal. Calc'd for C21H22C12N2O2 3
C, 50.40; H, 4.637 Cl, 14.17; N, 8.40; S, 6.41.
Found: C, 50.23; H, 4.63; Cl, 14.27; N, 8.34;
S, 6.46.
Example 18
1-[2-(2~4-dichlorophenyl)-2-(2~4-dichlorothio-
phenoxy~ethylthio)ethyi]-lH-imidazole hydrogen fumarate
(Table I, Compound No. 33). To a stirred solution
of sodium hydroxide (2.02 g, 0.050 mole) in ethanol
(180 ml) at 25 under a blanket of nitrogen, was
added l-[2-(2,4-dichlorophenyl)-2-(ethoxythiocarbonyl-
thio)ethyl]-lH-imidazole hydrogen oxalate (4.51 g,
0.01 mole). After stirriny at 25 for 0.75 hour,
chloromethyl 2,4-dichlorophenyl sulfide (2.5 g,
0.011 mole) was added. The mixture was refluxed for
eighteen hours and concentrated to dryness. The
residue was diluted with water and the mixture
extracted with two portions of diethyl ether. The
combined ethereal extracts were washed successively
with dilute NaOH, H2O, brine and dried (Na2SO4).
Removal of the ether left a cloudy oil (4.2 g) which
afforded 3.8 g of the pure free base after chromato-
graphy on silicic acid (100 g) with methylene chloride -
acetone (10:1).
The oily free base (3.8 g) was treated with fumaric
acid (950 mg) to give, after dilution with acetonitrile,
the fumarate salt which melted at 117-120 after
two recrystallizations from acetonitrile.
~155857
-48-
Anal. Calc'd for C18H14C14N2S2 4 4 4
C, 45.53; H, 3.13; Cl, 24.44; ~, 4.83; S, 11.05.
Found: C, 45.35; H, 3.09; Cl, 24.10i N, 4.68;
S, 11.04.
Example 19
1-[2-~4-biphenyly}methoxyethoxy)-2-~2,4-dichloro-
phenyl)ethyl]-lH-imidazole nitrate (Table I, Compound
No. 37). A solution of 1-~2-(2,4-dichlorophenyl)-2-
(2-hydroxyethoxy)ethyll-lH-imidazole nitrate (3.64
g, 0.01 mole) in DMF (22 ml) was added dropwise
during ten minutes to a stirred, cooled (ice-water)
mineral oil suspension of 57% sodium hydride (926
mg, 0.022 mole) in DMF (15 ml) under nitrogen.
Stirring was then continued at 40-45 for twenty
lS minutes to complete salt formation. The cooling
bath was replaced and a solution of 4-chloromethyl-
biphenyl (2.03 g, 0.01 mole) in THF (10 ml) added.
The mixture was then heated at an oil bath temperature
of 65 for three hours and concentrated to dryness.
The residue was partitioned between diethyl ether
and water. The ethereal layer was washed (brine),
dried (Na2SO4) and the ether removed. The residue
was dissolved in acetonitrile and the mineral oil
removed by washing with n-pentane (2x). The acetonitrile
was removed and the residue chromatographed on
silicic acid (120 g) with methylene chloride -
acetone (10:1) to give the free base (1.56 g) as a
yellow oil. A solution of the free base (1.56 g) in
ethyl acetate was treated with oxalic acid (300 mg)
to provide the hydrogen oxalate salt which melted at
113-121 after recrystallization from ethyl acetate
followed by recrystallization from nitromethane.
1 1~5~S ~
-49-
The hydrogen oxalate salt was partitioned between
diethyl ether and dilute aqueous sodium hydroxide. The
ethereal layer was washed (water, brine), dried (Na2SO4)
and concentrated. Treatment of a solution of the re-
sulting free base in ethyl acetate with 70% nitric acid~d=1.42) provided the titled nitrate salt mp 114-116.5.
Recrystallization from ethyl acetate gave colorless
crystals of the analytical sample, mp 115-118.5.
Anal- Calc d for C26H24C12N22-HN3
C, 58.88; H, 4.75; Cl, 13.37; N, 7.92.
Found: C, 58.67; H, 4.98; Cl, 12.89; N, 7.73.
Example 20
Chloromethyl 2,6-dichlorophenyl sulfide (Scheme III,
21, Z=Cl, n=l, Y=S, m=o, Rl'2=2,6-dichloro). Utilizing the
general method of Goralski and Burk*, benzyltriethyl-
ammonium bromide (0.6 g, 2.2 mmoles) was added to a
stirred mixture of 2,6-dichlorothiophenol (12.0 g,
0.067 mole) and powdered 85~ potassium hydroxide (4.42 g,
0.067 mole) in bromochloromethane (300 ml) at 22. An
immediate exotherm ensued, the temperature rising to
38. Stirring was continued at ambient temperature for
two hours. The mixture was filtered and the excess
bromochloromethane removed in a rotary evaporator to
leave an amber oil. A solution of the oil in diethyl
ether was dried (Na2SO4) and concentrated to leave the
crude product as a crystalline solid. Recrystallization
from Skellysolve-B afforded chunky crystals (11.9 g) of
the title compound, mp 52.5-55.5.
* J. Org. Chem., 42, 3094 (1977).
115S857
--so--
Example 21
1-12-(2~4-Dichlorophenyl)-2-(2 ! 6-dichlorophenYlthio-
methylthio)ethyll-lH-imidazole hydrogen fumarate (Table I,
Compound No. 39). To a stirred solution of ~odium
hydroxide (2.02 g, 0.050 mole) in ethanol (180 ml) at
25 under a blanket of nitrogen, was added 1-12-(2,4-
dichlorophenyl)-2-(ethoxythiocarbonylthio)ethyl]-lH-
imidazole hydrogen oxalate (4.51 g, 0.01 mole).
After stirring at 25 for 0.75 hour, chloromethyl
2,6-dichlorophenyl sulfide (2.5 g, 0.011 mole) was
added. The mixture was refluxed for eighteen hours
and concentrated to dryness. The residue was diluted
with water and the mixture extracted with two portions
of diethyl ether. The combined ethereal extracts
lS were washed successively with dilute NaOH, H2O,
brine and dried (Na2SO4). Removal of the ether left
a cloudy oil (4.4 g) which afforded 2.56 g of the
pure free base after chromatography on silicic acid
(150 g) with methylene chloride-acetone (10:1).
A solution of the free base (2.56 g) in acetonitrile
was treated with fumaric acid (632 mgs) to afford color-
less crystals (2.22 g) of the hydrogen fumarate salt,
mp 134-136. Recrystallization from acetronitrile gave
the analytical sample, mp 133-136.
Anal. Calc'd for C18H14C14N2S2.C4H4O4
H, 3.13; Cl, 24.44; N, 4.83; S, 11.05.
Found: C, 45.36; H, 3.02; Cl, 24.29; N, 5.00;
S, 11.03.
Example 22
1-12-(4-Chlorophenoxymethylthio)-2-(2,4-dichloro-
phenyl)ethyl]-lH-imidazole sesquihydrogen fumarate
-51- 1 1~5~ ~
(Table I, Compound No. 41). In a manner similar to
that described in Example 21, replacement of the
chloromethyl 2,6-dichlorophenyl sulfide with chloromethyl
4-chlorophenyl ether gave the title compound, mp 158-
160.
Anal- Calc d for C18H15C13N2S 1-5(C4H4O4) C, 49.04;
H, 3.60; Cl, 18.09; N, 4.77; S, 5.45.
Found: C, 49.28; H, 3.74; Cl, 17.74; N, 4.85;
S, 5.51.
Example 23
1-{2-[(4-Chlorophenylthio)methoxy]-2-[2,4-dichloro-
phenyl]ethyl}-lH-imidazole hydrogen fumarate (Table I,
Compound No. 40). 1-(2,4-Dichlorophenyl)-2-tlH-l-
imidazolyl)ethanol* (2.57 g, 0.01 mole) was added to
a stirred mixture of. a mineral oil suspension of 57%
sodium hydride (463 mgs, 0.011 mole) in DMF (15 ml)
and THF (10 ml), under nitrogen. The mixture was
heated under gentle reflux for 0.75 hour to complete
salt formation. The mixture was cooled in an ice-
water bath and a solution of chloromethyl 4-chlorophenyl
sulfide (1.93 g, 0.01 mole) in THF (3 ml) added. The
mixture was heated under gentle reflux for eighteen
hours and concentrated. A solution of the residue in
diethyl ether was washed successively with water,
Na2CO3-water, brine and then dried (Na2SO4) and
concentrated.
The residue was dissolved in acetonitrile and the
mineral oil removed by washing with n-pentane (2x).
Removal of the acetonitrile left a dark oil which was
chromatographed on silicic acid (120 g) with methylene
chloride-acetone (20:1) to afford a brown oil (1.79 g)
which crystallized. Recrystallization from cyclohexane
gave 1.5 g of the free base, mp 95-97.
*U.S. 3,717,655 and Godefroi et al, supra.
-52- 11S5857
Treatment of an acetonitrile ~olution of the
free base with umaric acid provided the hydrogen
fumarate salt, mp 128-130. Two recrystallizations
from ethyl acetate -Skellysolve-B - gave the analytical
sample, mp 129-133.
Anal- Calc'd for C18H15C13N2S C4H4 4
H, 3.61; Cl, 20.07; N, 5.29; S, 6.05.
Found: C, 49.80; H, 3.60; Cl, 19.99; N, 5.17;
S, 6.20.
Example 24
1-[2-(4-Chlorobenzylthiomethylthio)-2-(2,4-
dichlorophenyl)ethyl]-lH-imidazole hydrogen fumarate
(Table I, Compound No. 42). To a stirred solution of
sodium hydroxide (2.02 g, 0.05 mole) in ethanol (180
ml) at 25 under a blanket of nitrogen, was added 1-
[2-(2,4-dichlorophenyl)-2-(ethoxythiocarbonylthio)
ethyl]-lH-imidazole hydrogen oxalate t4.51 g, 0.01
mole). After stirring at 25 for 0.75 hour a solution
of 4-chlorobenzyl chloromethyl sulfide (2.07 g, 0.01
mole) in ethanol (2 ml) was added. The mixture was
refluxed for twenty hours and concentrated to dryness.
The residue was partitioned between diethyl ether and
water. The ethereal layer was washed successively
with H2O, Na2CO3-H2O, H2O, brine and dried (Na2SO4).
Removal of the ether left the free base (3.3 g~ as a
viscous brown oil. Treatment of a solution of the
free base (3.3 g) in acetonitrile with fumaric acid
(0.78 g) provided 2.5 g) of the title compound, mp
120-125. Recrystallization from ethyl acetate gave
colorless crystals, mp 121-123, of the analytical
sample.
1 15S857
-53-
Anal. Calc d for ClgH17Cl3N2s2-c4H4O4 C~ 49-34; H~
3.78; Cl, 19.00; N, 5.00; S, 11.45.
Found: C, 49.70; H, 3.90; Cl, 18.94; N, 5.24;
S, 11.39
Example 25
1-(2-[(4-Chlorobenz~lthio)methoxy]-2-[2 ! 4-dichloro-
phenyl]e~y_)-lH-imidazole hydrogen oxalate (Table I,
Compound No. 43). 1-~2-(2,4-Dichlorophenyl)-2-(2-
hydroxyethoxy)ethyl]-lH-imidazole (2.57 g, 0.01 mole)
was added to a stirred mineral oil suspension of 57%
sodium hydride (463 mg, 0.011 mole) in a mixture of
DMF (15 ml) and THF (10 ml). The mixture was heated
under gentle reflux for 0.5 hr to complete salt
formation. A solution of 4-chlorobenzyl chloromethyl
sulfide (2.07 g, 0.01 mole) was added and the mixture
heated under gentle reflux for twenty hours. The
mixture was partitioned between diethyl ether and
water. The ethereal was filtered to remove starting
alcohol (1.3 g~. The ethereal filtrate was concentrated.
A solution of the residue in acetonitrile was washed
with n-pentane (2x~ to remove the mineral oil. The
acetonitrile was removed and the residue chromatographed
on silicic acid (30 g) with methylene chloride -
acetone (25:3) to give the free base (190 mg) as a
viscous brown oil. Treatment of a solution of the
free base (190 mg) in ethyl acetate with oxalic acid
(40 mg) provided colorless crystals of the title
compound, mp 148-150. The product melted at 153.5-
154 after recrystallization from acetonitrile.
Anal. Calc'd. for C1gH17C13N2OS.C2H2O4: C, 48.71; H, 3.70;
Cl, 20.54; N, 5.41; S, 6.19.
Found: C, 49.21; H, 3.71; Cl, l9.9S; N, 5.30; S, 6.73.
1 155857
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The antimicrobial compounds of this invention
exhibit antifungal and antibacterial activity against
a wide variety of human and animal pathogens in addition
to those referred to in Tables II and III above and are
accordingly useful not only in pharmaceutical appli-
cations but also in agricultural, industrial, household
and other applications in which such activity i~ required.
In general, antimicrobial compositions may contain such
compounds in any concentrations, i.e. from about 0.1%
to about 99.9% in a suitable or conventional carrier
adapted for the intended use. For example, from about
10% to 90% concentrates may be supplied for dilution by
the user to concentrations generally ranging from about
0.1% to 10%.
lS In pharmaceutical formulations compositions may be
solid, semi-solid or liquid in for~ such as tablets,
capsules, powders, suppositories, liquid solutions,
suspensions, creams, lotions, gels, ointments and the
like. Pharmaceutically acceptable non-toxic carriers,
or excipients normally employed for solid formulations
include tricalcium phosphate, calcium carbonate, kaolin,
bentonite, talcum, gelatin, lactose, starch and the
like; for semi-solid formulations there may be mentioned,
for example, polyalkylène glycols, vaseline, petrolatum
and other cream bases; for liquid formulations there
may be mentioned, for example, water, oils of vegetable
origin and low boiling solvents such as isopropanol,
hydrogenated naphthalenes and the like. The pharma-
ceutical compositions containing the compounds of the
present invention may be subjected to conventional
pharmaceutical expedients such as sterilization and can
contain conventional pharmaceutical excipients such as
preservatives, stabilizing agents, emulsifying agents,
salts for the adjustment of osmotic pressure and buffers.
The compositions may also contain other therapeutically
active materials.
11~5857
-55- -
The pharmaceutical compositions of this invention
typically comprise a pharmaceutically acceptable, non-
toxic carrier in combination with one or more compounds
represent0d by formula 4 in an amount effective for
relief or prevention of the specific condition being
treated. Since the active compounds of this invention
exhibit anti-fungal and anti-bacterial activity over a
wide range of concentration, the efective amount may
vary. For example, in topical formulations the amount
may be about 0.1% to about 10~ of the total pharmaceutical
formulation while in other formulations the amount may
be about S to 95% or more. Preferably the pharmaceutical
compositions of this invention are formulated in unit
dosage form to facilitate administration (unit dosage
being the amount of active ingredients administered on
one occasion).
In pharmaceutical applications, the subject com-
pounds and compositions may be administered to humans
and animals by conventional methods, e.g. topically,
orally, parenterally and the like. "Topical" ad-
ministration includes intravaginal application while
parenteral administration includes intramuscular as
well as subcutaneous and intravenous injection. Intra-
venous injection of imidazole derivatives for certain
systemic conditions has been demonstrated to be effective
(see for example, Drugs 9, 419-420 (1975), which describes
the intravenous administration of Miconazole, i.e.
1-[2,4-dichloro-~-(2',4'-dichlorobenzyloxy)phenethyl]-
imidazole nitrate, to patients with systemic candidiasis).
Topical application is the preferred method of admin-
istration in pharmaceutical applications. For such
treatment, an area having an existing fungal or bacterial
growth, or to be protected against attack by fungi or
bacteria, may be treated with the subject compounds of
formula 4 or compositions containing them by, for
example, dusting, sprinkling, spraying, rinsing,
brushing, dipping, smearing, coating, impregnating
and the like.
11S58S7
-56-
The exact regimen for pharmaceutical administration
of the compounds and compositions disclosed herein will
necessarily be dependent upon the needs of the in-
dividual subject being treated, the type of treatment,
e.g., whether preventative or curative, the type or
organism involved and, of course, the judgment of the
attending practitioner. In general, for systemic
(e.g., oral or parenteral) administration it is
expedient to administer the active ingredient in
amounts of between about 1 and 100 mg/kg body weight
per day (preferably between about 5 and 50 mg/kg body
weight per day) preferably distributed over several
applications (e.g., in 3 individual doses) in order to
achieve effective results. For localized (e.g.,
topical) administration, however, proportionately less
of the active ingredient is required.
In agricultural applications, the subject compounds
may be applied directly to plants (e.g., seeds, foliage)
or to soil. For example, compounds of the present
invention may be applied to seeds alone or in admixture
with a powdered solid carrier. Typical powdered
carriers are the various mineral silicates, e.g.,
mica, talc, pyrophyllite, and clays. The subject
compounds may also be applied to the seeds in admixture
with a conventional surface-active wetting agent with
or without additional solid carrier. Surface-active
wetting agents that can be used are any of the conventional
anionic, non-ionic, amphoteric or cationic types. As a
soil treatment for fungi and the like, the subject
compounds can be applied as a dust in admixture with
sand, soil or a powdered solid carrier such as mineral
silicate with or without additional surface-active
agent, or the subject compounds can be applied as an
aqueous spray optionally containing a surface-active
1155857
-57-
dispersing agent and a powdered solid carrier. As a
foliage treatment, the subject compounds can be applied
to growing plants as an aqueous spray which contains a
surface-active dispersing agent with or without a
S powdered solid carrier and hydrocarbon solvents.
In industrial applications, the subject compounds
may be used to control bacteria and fungi by contacting
the pathogens with the compounds in any known manner.
Materials capable of supporting bacteria and fungi may
be protected by contacting, mixing or impregnating
these materials with the subject compounds. In order
to increase their effect, the subject compounds may
be combined with other pesticidal control agents such
as fungicides, bactericides, insecticides, miticides and
the like. A particularly important industrial/
agricultural use for the subject compounds of the
present invention is as a food preservative against
bacteria and fungi which cause deterioration and spoilage
of foods.
This invention has been disclosed with respect
to certain preferred embodiments, and it will be
understood that modifications and variations thereof
obvious to those skilled in the art are to be
included within the spirit and perview of this
application and the scope of the appended claims.
