Note: Descriptions are shown in the official language in which they were submitted.
7~
-- 1 --
Process for ~reparing n-trit~imidazole compounds
The present invention relates to a novel process
for producing N-tritylimidazole compounds. More parti-
cularly, the invention pertains to an improved process
for preparing N-tritylimidazole compounds of the formula:
2 ~¦ R3
~ C ~ 3 [I]
2 n 2
wherein Rl, R2 and R3 may each be the same or differ-
ent and represent a hydrogen atom, an alkyl group or a
phenyl group, X1, X2 and X3 may each be the same
or different representing an alkyl group or an electro-
10 negative moiety, and nl, n2 and n3 are each O or aninteger of 1 or 2.
The N-tritylimidazole compounds of the formula ~I~ are
already known to be useful as antimycotic or antibacterial
,
'. ~ .
j ~13~79
-- 2 --
agents [See U.S. patents Nos. 3,321,366 and 3,705,172].
As disclosed in these U.S. patents, the N-tritylimi-
dazole compounds may be prepared by reacting halides or
salts of tritylcarbinol derivatives with silver or sodium
salts of imidazole derivatives. However, this method has
certain disadvantages. For example, the halides and salts
of tritylcarbinol derivatives are unstable in water and
hence, difficult to prepare; the silver salt of imidazole
derivatives are expensive and unstable upon exposure to
10 light; and, moreover, the yield of the objective compounds
is low.
The N-tritylimidazole compounds may also be prepared
by reacting tritylcarbinol derivatives with imidazole
derivatives. Unlike the aforesaid known method, expensive
15 or unstable starting materials are not required in this
process, but the reaction must be carried out at a very
high temperature for a long period of time to obtain the
desired compounds even in low yields since the reaction
does not proceed smoothly under ordinary conditions.
20 Thus, this process is also unsatisfactory for commercial
production of the N-tritylimidazole compounds.
In order to provide a more convenient and economi-
cal process for the production of the N-tritylimidazole
compounds, an extensive study has been made, and it
25 has now been found that the reaction of tritylcarbinol
derivatives with tri(l-imidazolyl)phosphine derivatives
proceeds smoothly under mild conditions to give the
desired N-tritylimidazole compounds in high yields. It
has also been found that o-chlorophenyldiphenylmethanol,
30 which is used as the starting material for the produc-
tion of the very potent antifungal compound known as
"Clotrimazole" in the process of the invention, can be
obtained in a high yield by treating with water the
reaction mixture obtained by the Friedel-Crafts reaction
35 of o-chlorobenzotrichloride with benzene in the presence
of aluminum chloride.
~^` 111~179
-- 3 --
Thus, the present invention provides a process for
preparing the N-tritylimidazole compounds of the formula
[I], which comprises reacting a tritylcarbinol derivative
of the formula:
0~
~ C - ~ ~ 3 lII]
(Xl)n ~3 (X2)n2
1' X2, X3, nl, n2 and n3 are each as defined
above, with a tri(l-imidazolyl)phosphine derivative of the
formula:
3 ..
( N - y ~ p [III]
R2 '
10 wherein Rl, R2, R3 are each as defined above, in a
solvent at a temperature ranging from -5 to 130C.
In a preferred aspect, the invention provides a
process for preparing 1-[(2-chlorophenyl)diphenylmethyl]-
imidazole which comprises treating the reaction mixture, ~:
15 which is obtained by the reaction of o-chlorobenzotri-
chloride with benzene in the presence of aluminum
chloride, with water to give o-chlorophenyldiphenyl-
methanol and then reacting o-chlorophenyldiphenylmethanol
with tri(l-imidazolyl)phosphine.
In the foregoing and, where appropriate, in the
subsequent descriptions, the alkyl groups of Rl, R2,
R3, Xl, X2 and X3 may be straight or branched chain
alkyl groups having one to twelve carbon atoms, preferably
,
':
9~79
-- 4
having one to four carbon atoms. Examples of preferred
alkyl groups are methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, secondary butyl, etc. Examples of
the electro-negative moiety are halogen (e.g. fluorine,
chlorine, bromine, iodine), nitro, trifluoromethyl,
cyano, alkylthio and alkoxy. Examples of the alkylthio
and alkoxy groups are preferably those having one to four
carbon atoms.
In the process of the invention, the ~-tritylimidazole
10 compounds of formula [I] are prepared by reacting a tri-
tylcarbinol derivative of the formula [II] with a tri(l-
imidazolyl)phosphine derivative of the formula [III],
usually at a temperature ranging from about -5 to 130C,
preferably from about 0 to 100C in a suitable solvent.
In conducting the reaction, the tri(l-imidazolyl)phosphine
derivative lIII] is generally used in an amount of more
than l/3 mole per mole of the tritylcarbinol derivative
[II], but good results are obtained when 2/3 to 3 moles of
the tri(l-imidazolyl)phosphine derivative [III] per mole
20 of the tritylcarbinol derivative [II] is used.
Examples of the solvents used in the process are
aromatic hydrocarbons, such as benzene or toluene,
halogenated aliphatic hydrocarbons, such as chloroform or
dichloromethane, tetrahydrofuran, methyl isobutyl ketone,
25 dimethylformamide, pyridine, acetonitrile and a mixture
thereof.
The tritylcarbinol derivatives [II] and the tri-
tl-imidazolyl)phosphine derivatives [III] used as the
starting materials are already known and can be prepared
30 by the known methods [J.Org.Chem., 7, 392 (1942); J.Am.
Chem.Soc., 33, 531 (l911); Angew.Chem., 73, 143 (1961)].
The tri(l-imidazolyl)phosphine derivatives [III] can
be also prepared by reacting an imidazole derivative of
the formula:
-
9~79
-- 5
N
~ [IV]
2 3
H
wherein Rl, R2 and R3 are each as defined above,
- with phosphorus trichloride in the presence of an
acid-binder in a suitable solvent.
As the tri(l-imidazolyl)phosphine derivative lIII]
are sensitive to moisture, it is expedient to react them,
without isolation, in solution with the tritylcarbinol
derivatives [II].
The following Examples are given to illustrate the
10 present invention more precisely, but are not intended
to limit the present invention thereto.
Example 1
(A) Preparation of o-chlorophenyldiphenylmethanol:-
Benzene (380 ml) was charged to a flask and aluminum
15 chloride (88 g) was suspended therein. A solution of
- o-chlorobenzotrichloride (138 g, 0.6 mole) in benzene
(145 ml) was added dropwise over 2 hours while keeping
the temperature at 60C. After the addition was com-
pleted, the mixture was refluxed for 2 hours. The
reaction mixture was poured into water (600 ml), and the
! flask was washed with benzene (240 ml) and water (120
ml). The combined mixture was refluxed for 4 hours. The
organic layer was separated, washed with water (400 ml),
treated with charcoal (6 g) and filtered. Evaporation of
the benzene filtrate gave 172.6 g of o-chlorophenyldi-
phenylmethanol as a crystalline mass. Yield, 97.7 %.
M.P., 88.5 - 91.5C.
(B) Purificiation of o-chlorophenyldiphenylmethanol:-
Eighty grams of o-chlorophenyldiphenylmethanol (M.P.,
88.5 - 91.5C) obtained in (A) was recrystallized from
isopropanol to give 71 g of the pure compound having a
melting point of 92 - 94C.
, .
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-- 6 --
Elementary analysis: Calcd. for ClgH15OCl:
- C, 77.41 %; H, 5.13 %; C, 12.03 %. Found: C, 77.58 %;
H, 5.01 %; Cl, 12.30 ~.
Example 2
Preparation of l-(o-chlorophenyldiphenylmethyl)-
imidazole:-
o-Chlorophenyldiphenylmethanol (2.50 g, 8.5 mmole)
obtained in Example 1 (B) at 0 - 10C was added dropwise
to a solution of tritl-imidazolyl)phosphine (0.99 g,
10 4.3 mmole) in chloroform (30 ml). Water was added and the
mixture was extracted with chloroform. The extract was
washed with a 5 % aqueous sodium hydroxide solution and
water in that order, dried over magnesium sulfate and
evaporated to give the residue. Recrystallization from
15 acetonitrile gave 2.2 g of l-(o-chlorophenyldiphenyl-
methyl)imidazole. Yield, 75 ~. M.P., 142 - 143C.
Elementary analysis: Calcd. for C22H17N2Cl:
C, 76.63 %; H, 4.97 %; N, 8.12 %. Found: C, 76.53 %;
H, 4.65 %; N, 8.41 ~.
Example 3
Preparation of l-(o-chlorophenyldiphenylmethyl)-
imidazole:-
88.2 g (0.6 Mole) of phosphorus trichloride was addeddropwise with stirring at 0 - 10C to a solution contain-
25 ing 122.4 g (1.8 mole) of imidazole and 181.8 g (1.8 mole)of triethylamine in 1200 ml of chloroform and the mixture
was stirred for 1 hour. 172 g of o-Chlorophenyldiphenyl-
methanol obtained in Example 1 (A) was added to the
resulting solution and the mixture was refluxed for 1
30 hour. After cooling, water was added, and the mixture
was extracted with chloroform. The extract was washed
successively with water, a 10 % aqueous potassium
carbonate solution and water, dried over magnesium
sulfate, treated with charcoal (18 g) and filtered.
35 Evaporation of the filtrate gave 240 g of an oily
residue. Crystallization of the residue from
-- 7 --
acetonitrile (180 ml) gave 159 g of l-(o-chlorophenyl-
diphenyl-methyl)imidazole. Yield~ 77.1 %. M.P.,
142 - 143C. Recrystallization of the crude compound
from acetonitrile (330 ml) gave 144.2 g of l-(o-chloro-
phenyldiphenylmethyl)-imidazole. Yield, 69 %. M.P.,
143`- 144C.
Example 4
Preparation of l-(o-chlorophenyldiphenylmethyl)-
imidazole:-
1.51 9 (11 mMole) of phosphorus trichloride was added
dropwise to a solution containing 2.24 g (33 mmole) of
imidazole and 3.03 g (33 mmole) of triethylamine in 40
ml of chloroform at 5 - 15C, and the mixture was stirred
for 1 hour. 2.95 g (0.01 Mole) of o-chlorophenyldiphenyl-
15 methanol obtained in Example 1 (B) was added to the
solution and the mixture was refluxed for 2 hours. The
reaction mixture was treated in the same manner as in
Example 3 to give 3.10 9 of l-(o-chlorophenyldiphenyl-
methyl)imidazole. Yield, 90 ~. M.P., 140 - 142C.
Example 5
Preparation of l-(o-chlorophenyldiphenylmethyl)-
imidazole:-
1.51 g (11 mMole) of phosphorus trichloride was addeddropwise at 50 - 55C to a solution containing 2.24 g (33
25 mmole) of imidazole and 3.03 9 (33 mmole) of triethylamine
in 40 ml of toluene and the mixture was stirred for 1 hour.
2.95 g (0.01 Mole) of o-chlorophenyldiphenylmethanol
obtained in Example 1 (B) was added to the reaction
mixture and the mixture was refluxed for 2 hours. After
30 cooling, water (40 - 50 ml) was added thereto. The
organic layer was separated, washed with a 5 % aqueous
potassium carbonate solution and water in that order,
dried over magnesium sulfate and evaporated. Crystal-
lization of the residue from acetonitrile gave 2.76 g of
l-(o-chlorophenyldiphenylmethyl)imidazole. Yield, 80 ~.
M.P., 142 - 143C.
:- ' ' '
.-~ lilg~79
Examp]e 6
Preparation of l-(o-chlorophenyldiphenylmethyl)-
imidazole:-
3.92 9 Of phosphorus trichloride was added dropwise
to a solution containing 4.48 g of imidazole and 6.96 g oftriethylamine in 80 ml of acetonitrile at room temperature,
and the mixture was stirred for 1 hour. o-Chlorophenyl-
diphenylmethanol (5.90 g) obtained in Example 1 (B) was
added, and the mixture was refluxed for 2 hours. The
10 solvent was evaporated, and the residue was refluxed for
2 hours. The solvent was evaporated, and the residue was
extracted with chloroform. The extract was treated in the
same manner as described in Example 3 to give 5.72 g of
l-(o-chlorophenyldiphenylmethyl)imidazole. Yield, 83 %.
15 M.P., 142 - 143C.
Example 7
Preparation of l-(o-chlorophenyldiphenylmethyl)-
imidazole:-
3.43 g Of phosphorus trichloride was added dropwise at
10C to a solution containing 10 g of imidazole in 50 mlof chloroform. After the mixture was maintained at 5 -
lO~C for 1 hour, imidazole hydrochloride was precipitated
and filtered off with suction, and the filtrate was con-
centrated. o-Chlorophenyldiphenylmethanol (7.08 g) was
; 25 added, and the mixture was heated at 40 - 60C for 5 minutes. Water was added, and the mixture was extracted
with chloroform. The extract was treated in the same
manner as in Example 3 to give 6.95 g of l-(o-chloro-
phenyldiphenylmethyl)imidazole. Yield, 84 ~. M.P.,
140 - 142C.
Example 8
Preparation of l-triphenylmethylimidazole:-
The reaction was carried out in the same manner as inExample 3 except for using triphenylmethanol in place of
o-chlorophenyldiphenylmethanol. The obtained crystalline
residue was washed with isopropyl ether to give crude
- -,
.
- 9 - :
l-triphenylmethylimidazole. Yield, 98.4 %. Recrystalli-
zation from acetonitrile gave pure l-triphenylmethylimida-
zole in 83 % yield. M.P., 220 - 221C.
Elementary analysis: Calcd. for C22H18N2:
C, 85.13 %; H, 5.85 % N, 9.03 %. Found: C, 85.10 %;
H, 5.69 %; N, 8.97 %.
Example 9
Preparation of l-triphenylmethylimidazole:-
The reaction was carried out in the same manner as in
10 Example 7 except for using triphenylmethanol in place ofo-chlorophenyldiphenylmethanol. Recrystallization of the
obtained crystalline residue from acetonitrile-chloroform
gave pure l-triphenylmethylimidazole in 90 % yield.
M.P., 220 - 221C.
Example 10
Preparation of l-triphenylmethylimidazole:-
The reaction was carried out in the same manner asin Bxample 2 except for using triphenylmethanol in place
of o-chlorophenyldiphenylmethanol. Recrystallization
of the obtained crystalline mass from acetonitrile gave~
pure l-triphenylmethylimidazole in 81 % yield. M.P.,
219 - 220C.
