.- ` ~ !
73
DESCRIPTION OF ~'HE: IN~ .NTION:
The invention relates to novel imidazole derivatives having
the formula~
;~o ( I ) ~,
R
S and the th~ra}~eutically acceptable acid addition salts thereof, wherein:
~r i9 a member s~lcected from the group con~i~ting of phenyl, sub~tituted
plhenyl, thienyl, halothienyl and naphtllyl, and wherein aaid
sub~tituted phenyl i8 phenyl having from 1 to 3 sub~tituent3 , r~
independently selected Irom the group consi~ting of halo,
lo~veralkyl, loweralkyloxy, nitro anct cyano; and .
.
1:2. i6 a member selected from the group consisting of allcyl having from ~:
2 to about 10 carbon atolns, alkyloxymethyl wherein the al~yl- -
group has from 1 to about 10 carbon atoms, ~lkenyl, alkenyl-
oxymethyl, wherein said alkenyl has from ~ to about 10 carbon ~
atoms, hydroxymethyl, 2-propynyloxymethyl, halomethyl, aryl, .
arylloweralkyl, aryloxymethyl, arylthiomethyl and arylmethoxy-
methyl, wherein said aryl i~ a member selccted from the group ; .
consi6ting of phenyl, substituted phenyl, naphthyl, and mono- and
di-halonaphthyl and wherein said substituted phenyl is phenyl ~
having from 1 to 3 substituents indcpcndelltly ~elected from the ::
- group consisting of halo, loweralkyl, loweralkyloxy, cyanoj nitro, ,
phenyl, phenylmethyl, benz;oyl, l~alobenzoyl, loweralkylcarbon~l, .loweralkyloxycarbonyl alld trifluoromethyl, provided that when
more than one substituents are present only one thereo may be
~elected from the group consisting of phenyl, ph~inyLmethyl,
benzoyl and halobenzoyl.
.; ' ,~, ,
t
;_
. . ; .
. ' ' ~ ~;' '.
--2--
. .
`.`
873
More particularly "alkyl" as used in the definition of R
is meant to incl~tde straight and branch chained hydrocarbon radicals
having from 2 to about 10 carbon atoms, such as, for example, ethyl,
propyl, l-methylethyl, l,l-dimethylethyl, butyl, pentyl, hexyl, heptyl,
octyl, decyl and the like alkyls; "alkyl" as used in the definition of
alkyloxymethyl is meant to include straight and branch chained hydro-
carbon radicals having from 1 to about 10 carbon atoms, such as,
for example, methyl and the alkyls mentioned herebefore;
"loweralkyl" as used herein has the meaning oE a straight or branch
chained alkyl radical having from 1 to about 6 carbon atoms, such as,
for example, methyl, ethyl, propyl, l-methylethyl, l,l-dimethylethyl,
butyl, pentyl, hexyl and the like alkyls; "alkenyl" as used herein
refers to straight and branched chained alkenyl radicals having from 2
to about 10 carbon atoms, such as, for example, ethenyl, 2-propenyl,
2-butenyl, 3-butenyl, 2-pentenyl, 2-hexenyl, 2-decenyl and the like
alkenyls; and the term "halo" is generic to halogens of atomic weight
less than 127, i.e., fluoro, chloro, bromo and iodo.
The compounds of formula (I) are conveniently prepared by
reacting imidazole (II) with an appropriate reactive ester of formula
(III) wherein Ar and R are as previously defined and wherein W is a
reactive ester function, such as, for example, halo, 4-methylbenzene-
sulfonate, methylsulfonate and the like. Preferred reactive esters are
halides and more particularly bromides and chlorides.
In one method of conducting the reaction between imidazole
and ~III), imidazole is first transformed into a metal salt thereof
by treatment with an appropriate metallating agent such as, for example,
a metal alkoxide, e.g., sodium- or potassium methanolate, or a
metal hydride such as sodium hydride. The thus obtained metal salt
is then reacted with (III) in an appropriate organic solvent, such as,
.
S~3
for example, dimethylformamide or dimethylacetamide. A small
amount of a metal iodide, such as sodium or potassium iodide may
advantageously be added to promote the reaction, especially when
the reactive ester is a chloride or bromide.
Alternatively, the reaction of imidazole with the reactive
ester (III) may also be carried out without previous salt formation,
by bringing the reactants into contact with each other in an appropriate
organic solvent such as, Eor example, dimethylformamide or dimethyl- ;
acetamide. In these circumstances it is appropriate to use an excess
of imidazole or to add to the reaction mixture an appropriate base
such as, for example, sodium or potassium carbonate or bicarbanate
in order to bind the acid which is liberated during the course of the
reaction. The use of an excess of imidazole is however preferred.
Further it is advantageous to conduct the reaction in the presence
of a metal iodide such as, for example, sodium or potassium iodide.
In each of the above procedures, somewhat elevated
temperatures may be employed to enhance the rate of the reaction
and most conveniently the reactions are carried out at the reflux
temperature of the reaction mixture.
In these and the following preparations the reaction products :
may be isolated from the medium and, if necessary, further purified
according to methodologies generally known in the art, such as, for
example, extraction, trituration, crystallization, chromatography, etc
The foregoing procedures are more fully illustrated by the
following schematic representation:
. .
~6~873 ~ 1
;
N NaOCH ~midazole t O ¦~
3 ~ ~sodium sal3 R I 9 t
~II3 ~III)
~l DMF ~
( I ) _
.
(II ) t (III ) NaI ' !~.
DMF ~
' . ~
An additional method of preparing the compound6 of formula
( I ) is by the ketalization of an appropriate aroylmethylimidazole of
Iormula (I~ ) wherein Ar has the same meaning as assigned to it -
previously ~'~ith an appropriate diol of forlnula ~V ) wherein R i8 as
previously defined.
~;'
Said ketalization reaction may be carried out following ~,
methodologies analogous to those described in the literature, e. g.,
for the preparation of 2-bromomethyl-2, 4-diphenyl l, 3-dioxolane ~'
~S~mthesis, 19i4 ~I), 237. s~
E~
In a preferred manner of carrying out the rcaction both , ~-
rcactants are re1uxed together Ior several hours with azeotropic
water removal in an appropriate organic solvent, preferably in the i~
presence of a simple alcohol, such as, for example, ethanol, propanol,
butanol, pentanol and the like, and in the presence of as~ appropriate
strong acid such as ~-methylbenzenesulfonic acid,Suitable orgallic
solvents are, for exampl~e, aromatic hydrocarbons, such as benAene,
ethylbenzene, dimethylbenzene and the like and saturated hydrocarbons,
such as cyclohexane. ,'
~ . .
- 5 ~
I''
' I
j.
., .. . . . . ~, .
,. .~
1~6 51~ ~ 3
L
The foregoing reaction may be illustrated as follows: ~;~ -
~N~J 0 OH 4-methylbenzene- .
CH2-C-~r + R-C~-CH2 oH sUlfonic acid (I ) ~;~ .
butanol
IV ) ( V ) be~lzsene
.,
The compounds o:~ formula ~ I ? wherein R represents an
alkyloxymethyl, alkenyloxymcthyl, Z-propynyloxymetllyl or arylmethoxy_ i~
methyl radical, (I-a), mayotillby prepared by the reaction of an appropriate
compound of formula ( I ) whereill R is hydroxymethyl ( I-b ) with .
an appropriate reactive ester of formu]a (VI ) wherein Rl i6 selected from
the group con9isting c~f alkyl, alkenyl, 2-propynyl and arylmethyl and
W iB a reactive ester ~unction as previously defined, according to
common 0-alkylating procedures. Preferably the reaction is carried:
out in a suitable organic solvent such as, for example, dimethyl-
Iormamide or dimethylacetamide in the presence of an appropriate ~.
~trong metal base such as, Ior example, sodium hydride, sodium !.,
carbonate, potassium carbonate and the like,
~NJJ . - ~N J ~.
~ DMF 1 _~
HOCH2 1 1 (VI) R -0-CH2 r
(I-b) (I-a)
. ~
5~_
-- .
~ ..
-6- - !~
-- '
~5~3
The compounds of formula (I ) whcrcin R stands for
alkyloxymethyl, ( I-c ), may still bc prepared by the condensation
of (I-b) with an appropriate alkanol. Said condensation reaction
may be carried out by refluxing the reactants together ~lnder
azeotropic water removal in an appropriate organic solYC!nt SUCII l ~'
as, or example, an aromatic hydrocarbol1, e.g., benzene, _~
methylben~senc, dimethylbenzene and the like, a saturat~d hydro- ~
carbon, e. g., cyclohexane, or in tha alkanol itself, in the presence ,j
of an appropriate strong acid, ~uch as, or exa~nple, 4-methyl- ~, L
benzenesulfonic acid.
.
N
4 methylben~cne- ~N~
( I-b) + alkyl-OH sulIonic acid
dimethylben~ene O Q
alkyl-O-CH2 1 ---I .
( I- c
;
Those compounds of formu1a ( I ) wherein R represents
alkyloxymethyl, alkenyloxymethyl, 2-propynyloxyn~ethyl, arylmethoxy- 5
methyl or aryloxymethyl, (I-d), nlay still be prepared bythe reaction of an
appropriate reactive ester of forlnula (VII) wherein A1 and W are as; defined
hereinbeorc with an appropriate hydroxy compound of the formula ` , ~t'
(VIII ) wherein R2 is selected from the group consisting of alkyl,
alkenyl, 2-propynyl, arylmel;hyl and aryl according to common
O-alkylating procedures as described herebefore.
~';
- . " ,, - ~
- . r
. . . .
~L065873
~N ) ~ N
o~o + R2-OH I52C3 CH2 Ar
W-GH2~ (VIII) RZ-O-CH2~1 ¦
(Vll) (I-d) ~,
The imida~ole derivatives of iormula ( I ), obtained in ~ L
ba6e form in the foregoit~g preparations, may be converted to ~;
their therapeutically useful acid addition salts by reaction with an
appropriate acid, as, for example, an inorganic acid such as
hydrohalic acid, i, e., hydrochloric, hydrobromic or hydroiodic
acid; sulfuric, nitric or thiocyanic acid; a phosphoric acid; an
organic acid such as acetic, propanoic, hydroxyacetic, o:-hydroxy-
propanoic, 2 oxopropal~oic, ethanedioic, propanedioic, 1, 4-butane-
dioic, (Z3-2-butencdioic, (E)-2-butenedioic, 2-hydroxy-1, 4-butane- ,~"
dioic, 2, 3-dihydroxy-1, 4-butanedioic, 2-hydroxy-1, 2, 3-propane- ~;
tricarboxylic, ben ~oic, 3-phenylpropenoic, a-hydroxybPn~eneacetic, i
methanesulfonic, ethanesulonic, 2-hydroxyethanesulfonic, 4-methyl-
benzenesulfonic, 2-hydroxybenzoic, 4-arnino-2-hydroxybenzoic, 2-
phenoxybenzoic or 2-acetyloxyben~,oic acid. The salts are in turn ~
convert~d to the corresponding free bases in the usual manner, e. g., ~'by reaction with alkali such as sodium or potassium hydroxide.
. ~.
.
The intermediates of formula ( III ) may be prepared by '
Rubjecting an appropriate ketone of fornlula ( IX ), wherein Ar and
W are as previously defined to a ketalizatioll reaction with an
appropriate diol o formula ( V ) in the same manner as de~cril~ed
hereinbefore for the preparation of the compounds ( I ) starting from ~L
(IV) ~nd (V). . ~,
.
r -
- 8 - r
~. .
' '
~6S873
Il 1 4-methylbenzencsu]fonic acid
W-CH2_C_Ar +R-CH-CH20H . _ _ ~ ( III )
butanol
benzenc
( IX ) ( V )
~,'
Alternatively the intermediate~ of formula ~ III ) are con- . 1~;
veniently prepared by transketalization o a ketal derivative of
a lcetone of formula ( IX ) fiuch a~, for example, a loweralkyl ketal
or a cyclic loweralkylene ketal, with a glycol of Iormula (V )
un~er conditions similar to those described hereinbefore or the direct ~;
ketalization, The loweralkyl kPtals and c~clic lowerallcylene ketals ~
used herein a~ starting materials are easily obtained by ketali~,ation ~ ~v
of a ketone of Iormula ( IX ) with a lower alkanol or al]<ancdiol according
to methodologies known in the art, A nun~ber of such compounds and
methods of preparing the same are described in U. S. Pat. Nos.
3, 575, 999 and 3, 717, 655.
. ~
The intermediates of formula (III) wherein Ar, R and
W are as previously defined, provided that when said Ar is phenyl,
then said R i6 other than phenyl, are deemed-to be novel and as
useful intermediates herein they con titute an additional feature of
thi s invention .
A number of the precursor glycols of formula (V ) are ~"
known and they may all be prepar~d according to known procedures ~.
as described in the literature~
In general they may be derived from the corresponding 2-R~oxirane~s ~
of formula ( X ) by hydrolytic cleavage of the o~tiranç nucleus with ~,
an appropriate strong acid ~uch as, for e~ample, ethanedioic acid,
sulfuric acid, hydrochloric acid and the like.
.
P~ ~
'~,
_ 9 _
,
. .
~'~
... ..
.
873
~o\ .,
R ~ (COOH)2 > (V)
(X) H20/1,4-dioxane
The oxiranes of formula (X) may in turn be obtained in a variety of ways.
Those of formula (X-a), wherein R3 stands Eor alkyl or
arylloweralkyl may, for example, be prepared by oxidizing an
appropriate alkene or arylaLkene of formula (XI) wLth an appropriate
oxydizing agent such as, for example, a benzeneperoxoic acid~
e.g., 3-chlorobenaeneperoxoic acid.
O~ "
Cl
(XI) (X-a)
~lternatively intermediates of formula (X-a) may still be obtained by:
i) converting an appropriate halide of formula (XII) wherein
R4 is alkyl or arylloweralkyl, having one carbon less than
in the corresponding R3, into a Grignard complex with
magnesium~
ii) reacting said Grignard complex with an appropriate 2-halo-
methyloxirane of formula (XIII) to obtain a ~-halomethyl
- alcohol compound of -formula (XIV); and
iii) performing ring closure of (XIV) by treatment with alkali;
- e.g. with sodium hydroxide in an appropriate solvent such
as, for example, 2,2'-oxybispropane.
--10--
. ............. . - . : . : :
; ' : ' .: . : . . ' . : : - . - :
;. .: . : .. : . , :, . .:,
-~
!
~Q~ 73
~.
The ~oregoing sequencc of reactions is more f~lly ~;
illustrated in the ollowing schematic representation:
O
R -halo ~ r Mg 1 ~ halo-CH2~
Lsolvent, ~
( XII ) ( XIII )
..
OH o
R - CH2 ~ CH - CH2halo ~ ~ , R ~ H
2, 2'-oxybispropane
(XIV) (X-a) 7 ;.,.
.
.,
l'hose intermediates of formula ( X ) wherein R is alkyloxy-
methyl, alkenyloxymethyl, 2-propynyloxymethyl, arylmethoxymathyl
S or aryloxymethyl, (X-b), are conveniently obtained by the reaction of
an appropriate hydroxycolnpound of formula (XV) wherein R5 is alkyl, r-_
alkenyl, 2-propynyl, aryl or arylmethyl ~ith an appropriate 2-halomethyl- 3
oxirane oI formula (XIII) following common O-alkylatingJ procedures as
geNerally known.in the art. .
Intermecliate~ of formula (X~ wherein R stands for aryl-
thion~ethyl, ( X-c ), may be prepared in an analogous manner by the
S-alkylation o an arylthiol of formula ( XVI ) with a 2-halomethyl-
oxirane of formula ( XIII ).
The foregoing reactions are ~chernatically illustrated hereafter: ;~
' O ,0 ' ~ .
R5-O~1 + halo-CH2 / \ 2 3 _ ~ R5-o-CH
2 -propanone
( XV ) ( XIII ) ( X-b )
- ' ~
E~
t
--1 1 -
'
,; .
. ..
, ' " ` ' '.
~c;5~73
l~ryl-SH + ~ XIII ) _~3_ ~ Aryl-S-CH~
2-propanone
(XVI~ (X c)
~'
Intermediates of formula (V ) wherein R ~tand~ for alkenyl
may, for example, be prepared starting ~rom an appropriate hydroxy-
alkylsub6tituted ethanediol by ketali~.ing the ethanediol group with
an appropriatl~ lcetone, e.g,, 2-propanone, converting thereafter
tlle remaining hydroxy group on the alkyl chain illtO a methane- ~
6ulfonate group by the r eaction with methanesulfonyl chloride, ~;
~plitting off met1lanesulfonic acid by treatment with an appropriate ~ ¦
fitrong ba6e such as, for example, sodium hydride in a suitable
solvcnt such as dimethylformamide, and finally liberating the free
diol rom the ketal by treatmen1 with an appropriate strong mineral
acid such as, for example, hydrochloric or 6ulfuric acid.
In a preferred Inanner o carrying out the aforementioned
reactions, the ketone used in the ketalization step is an internlediatç:
of formula (IX ,~ whereby the alkenylsubstituted dioxolanes of formula
( ~II ) are directly obtained in the course of the foregoing reaction "
~ equence,
~.,
The precursor arylketones of crmula (IX ) are generally
known and may be prepared according to known procedures as
described in the literature, IIL
20, Bromides are, for example, easily obtained by the bromination of
the corresponding methyl aryl methanone with bromine. ~;
The aroylmetl ylsubstituted imidazoles of formula ( IV ),
a number of which are described in U.S. Pat, NOB.
3, 71 7, 6 55 and 3, 65y, 8 1 3, ar ~ con~-nientl j pr epared by the reactio~ .
- l Z
. .
~ . .
- ~
'73
of ( IX ) with imida~ole in an analogous Inanner as previously
described for the preparation of the colnpounds ( I ) starting fron
imidazole and ( III ). -
The reactive esters of formula (VII~, used as intermediates
in the preparation of the cornpounds ( I-d ) are easily obtained by con- ~,
vertin~ the corresponding alcohol of ormula ( I-b ) into a reactive
ester thereof according to methodolo~ies generally l~nown in the art.
For example, methan~sulfonatos,and a.-rnethylbenzenesulc)nates are
convenicntly prepared by the reaction of the alcohol with rcspeetive~y
methanesulfonyl cllloride or ~-methylbenzenesulfonyl chloride and
halides may be prepared by the reaction of the alcollol witll an
appropriate halo~enating a~ent such as, for e~ample, sulIuryl
chloride, phosphor pentachloride, phosphor pentabromide, phosphoryl
chloride and the like. When the reactive ester is an iodide, it is
preferably prepared from the corresponding chloride or bromide by 1;he
replacement of that halogen with iodine.
From formula ( I ) it i9 evident that the compounds of this invention
have two asymmetric carbon atoms in their structures, namely 1;hose
located in the 2- and 4-position of the dioxolane nucleus, and consequently 1
they exist under different stereochemical optical isomeric forms.
Th~ stereochemical optical isomeric forlns of ( I ) and the therapeuti-
cally active acid addition ~alts thereof are intended to be within the
s cope o this invention.
:
The diast~reomeric raCelnateS of (I ), dcnoted as cis and i
trans ~orms respectively, accordin~ to the r.ules described in
~Narning and Indexing of Chemical Substances for Chemical Abs1racts
during the 9th CollecSive Period ( 1972-1976 )", published in C.A.
1972, 76, Inde~; Guide Section IV, p~ 85, lnay be obtained separately
by conventional methods. Appropriate methods whicll may advantageously
be enlployed therefore include, ~or exalnple, selcc1ive crystallizatio~
~ .
. , .
-13- '
_ -
.. . . . . . . . . . ..
;'3
and colu~nn chromato~raphy, For a numbcr of compounds the sterco-
chemical configuration was experimentally determined. In the re-
maining cases it i~ conventionally agreed to designate the stereo-
chemical form which i9 fir~t isolated as "A" and the second as "B",
without further reIerencs to the actual stereochemical confi~uration,
Since tlle asymmetric carbon atoms are already present in
the intermediates (III) it ia also pos~ible to separate ci~ ~nd tra
forms, or generally ~'A~' and ~B~ forms at this stage, wherettpon thc
corresponding Iorrns of (I) may be obtained alter reaction of the fore-
going with imidazole as previously described. The separatlon of cis;
and trans Iorms of (III) may be performed by conventional methods
as described hereinbefore for the separation of thc compounds (I )
into their cis and trans forms.
When R in the in~ermediates of forlnùla ( III ) has the meaning of a
hydroxymethyl ~roup it may be advantageous to esterify Iirst ~aid
hydroxymethyl group ~ith an appropriate acylhalide, e. g., benzoyl
chloride whereupon the thus obtained esters are separated into their ~"~
cis and trans forms, from which the acyl group is subsequently
splil oI hydrolytically in alkaline medium yielding the corresponding
forms of the desired hydroxymethylsubstituted intermediates of
Iormula ( III ).
It is evident that the cis and tran9 diastereomeric racemales .~.
may be further resolved into their optical isomers, cis ( ~), cis ( - ),
trans ~ +) and trans ( - ) by the application- o~ methodologies kno~vn to
tho~e skilled in the art.
i~
.
. ...................................................................................... . ,
-14-
_'~'~~
; .-~
1065B73
~`
The compounds of formula ( I ) and the acid addition salts gb~
thereof ~re useful agent9 in combatting fungi and bacteria. A6 such _
they are valuable in the treatment of human beings, animals and
plants suffering from pathogenic microorganisms and ini the destruc-
tion of microorganisms on materials.
The brc>ad spectrum of antifun~al and antibacterial activity of the ;~
compounds of formula (I) i~ cleiarly illustra1ed by the experimental ~i
data pre6ented hereafter, The compounds in the tabl~s are not listed
for tho purpo~e of limiting the invention thereto, but only in order
to e~emplify the useful properties of all the eompound~ within the
~cope of orrs ula ( I ),
The test for antifungal activity was performed using
Sabouraud's liq-lid medium in tcst tubes cach conlaining 4. 5 ml of
lic~uid medium, autoclaved at 120C for 15 n~inutes. The substances
were dissolved in 50% ethanol at a concentration o 20mg/ml and
subsequently diluted with ~terile distilled water to a concentration of
I Olng/ml, SuccessiYe decimal dilutions were then made with distilled
water to give a 6eri~is o~ stock solutions. To each tube containing 4. 5 ml
of Sabouraud's liquid medium was added 0. 5 ml of one of the ~tock
~olutions to give a concentration of the drug under investigation of
100 3~g, 10 ~g, 1 yg or 0. 1 Jlg per ml of medium.
Fiiamentous fungi were incubated at 25C for 2 - 3 weeks. A ~quare
block of side 2 mm. was excised and inoculated into the liquid medium.
~ three-day old culture on Sabouraud~s liquid medium was used for
yeasts, and the inoculumwas 0, 05 ml per tube. All the cultures were ~.'
incubated at 25C for 14 days. The final readings were taken after~ ~t~
two weeks and are summarized in the Table~ A as follows:
Ci~
~+~+ = complete inhibition of growth at 0.1 ~g/ml
+++ = complete inhibition of gro~Yth at 1 )lg/ml
3a +~ = complete inhibition of growth at 10 ,ug/ml
-~ = complete inhibition of growth at 100 ~g/ml . p,~
0 = no effect, i. e. growth was obserYed at the
llighest ~oncentration te~ted (100 ~lg/~nl).
., ~ t~' ' .
-15- ~ i
_
.. .
~ ~ i
1~)65873
In a first scrccning thc drugs und~:r inve~tigation were tested againæt i~
the following 11 fungi: _
1. Microsporum canis (M, c, in the tables)
2. Ctenomyces mentagrophytes (CtO m. in the tables)
S 3. Trichophyton rubrum (Tr. r. in the tables)
4. Phialophora verrucosa ~Ph. v. in the tables) E~;
5. Cryptococcus neoormans (Cr. n. in the tables) i;G~
6. Candida tropic~lis (C.tr. in the tables)
7. Candida albicans (C. alb. in the tables)
; 8. Mucor species (Muc. in the tables)
9. Aspergillus fumigatus (A. f. in the tables)
10. Sporotrichum schenckii (Sp. s. in the tables)
11. Saprolegnia species (Sap. in the tableæ)
.'
.
A number of the substances showing activity a~ainst t}ie
~hycomycetes Mucor at the lOpg/ml concentration were also tested
against four other species of phyco~nycetes, namely: i ~_
~'
1. Absidia ramosa (Abs. r. in the tablcs)
2. Basidiobolus meristosporus (Bas. m. ln the tables) ~
3. Mortierella species (Ms)rt. in the tables~ ~ -
4. Rhizopus (Rhi,in the tables). ~ -
~
The method used in this second screen was exactly the ~ame as
de~cribed above, and the results are given in Tableæ B.
. .
. ~i
. ~
'. ' ' ' '~,,.
- 1 6 ~
.
~.
-
- .
~S~3~73
.
Bactericidal tests were performed.on cultures on phenol
red dextrose broth Difco medium. The sane decimal dilution
techniques as described herebefor~ were used. The inoculum
consisted of a platinum loop (5 mm. diameter) fron~ a 24 hour
broth culure,
48 Hour6 after incubation, ~ubcultures were made frorn each culture .
and for the asses6ment of the bactericidal activity of the drugs wlder
investigation the presence or absence of growth after 7 days incubal;ion
was scored as described above.
'rhe substances were tested against the following gram-ncgative bacilli:
F~
l. Salmonella pullorum gallinarum (SPG in the tablc)
2. Escherichia coli (E. coli in thc table), and
3. Pseudomonas aeruginosa (PB. aer, in the table);
and against the ollowing gram-positive bacilli and cocci:
1. Ery~ipelothrix insidiosa (E. ins, in the table),
2. Staphylococcu6 hemolyticus (Staph. in the ta~le3, and ,
3, Streptococcus pyogenes (Strept. in thc table)~
The results are summariz:ed in Table~ C,
~'
,: : :
~, .
'~
~ - 1 7 -
~.''
"~ .
, ~.
...
__ t~ +++++++~
O^ ++t++ +ttt+++++ ++ I
~ .
¢a~ :+t ++ + + ++ +~ + +~ + +
__ ~ ~
~q' + -t + o-t -t -t + -E + + o + ', `
_ ....................... , ':
~ ~ + -t + O O + O O + O O O +
H __
~~1~ tOO +0000 + + ~ .
~1 ~I . . ~ . .
~C: ~~+++++~ `
Z ~' ~_~ ++++++++++I+I
H æ~z_XC`I ~ rî ++ ++ + + ++ ++ ++ + + + E ++ + I :
.
~`, +++++++++~+++++++++++',
o
~1 ++t++++++++++++~+
~1 1 '( I ~1 1 ~I -1 ~1 1 ~1 1
I ~
- - ,
¢ ~
c~ ~ c~ 4 ~ o ~ c~
-18
,,
- ~ ~::
- ~
+++++++++$$+$+~+++
~oô ',~
$+++$++$$++o++*$+-+~$_ _ :
~ + $+ + +, +-+ + +*+ -++ *++ -++ + -~+ ++++ -E -++ +*+
__ _
~ ++-~+++++t+++o+$+++tt+
H .___ :~
+ o + + oo + o -l- + 0 0 + 0 + l+- + -~ ~
__ _ _ . , '
H+0000+++++00+000++
~ ~ ~A $+$++$$++++++o+++~$$+
~ ~ ++++++++++oo++++++ ~' ' '
~ $++++++$$++++~+++++$+$+$+*+$++++++
. _
$++++$$$+++$+++$++~+$$++$$+++
v~ +t+$$+$$++*$$+$++$$$*$$+$*
_
C~
F~ ~
Y ~ y, ~ ..
C`l ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ..
c ~
~ .
-E~ ~ _ _ _
--19--
~;S15~3
-- ' A
~ O+++++ ++0+++++++0 1 ~'
_ j , .'
0~ o+t+ot+ +tOt++++ttt+ j
'~ o+++++ -+~to++++t+++~+-+~j '
_ ~
~_~ o + + + ~ + -+1- + O O + O + O t+~ O + I "' , '
'-- j .", ~ '; '
I .' ' '
i~ ~_ o+ooooo+o tooooooo 1l ;
E~ _ j ~:
~ _, oooooo ooooooooooo j :
~ ~ ~++t++++ +t+++++++++++ i
~ ~ ¢ P~
E~ \~0~ ,~ o+o++o+ ++o+o+++O++ I "'
'C /\o_ ~
.
~Z ~ ~Z~ :~ I ~ ~_ ~
+ + ++ + + $ ~+ + +++ ~$ ~ $ +$ + ~+ $+ +
~ ++$+++ +$o++$++-~+$ i
_ ' .
~ . 0aa0 0 a
0 t.) CJ ¢ P~ F4 ¢ ~ 1:~ C Fq ~
C~
I
~'~ ~ ~ `~
P: X ~ ~ ~ ~ I O ~ O ~ C~ ~ I
~1
E~ ~ ,
--20--
1~6SB73
_
.
~,, +
~ ,, + + + + ~ + + +
U~-- + + + + + + + + + + + + + + + + + + o o + + + + o + +
~ . - .
tn_ +
.o + + + + + + +
~ + + + + + + + + + + + + + + + + + + + + + +
U~-- ++ + + + + + ,, + + + + + + + + + +oo+ + + +o+ + I .
._ ~
4~ ~ + + + + + +
._ +~ + + + + + + + + + + + + + + ++ + + + , ..
+ + + + + + + + + + + + ~ - + + -1~ 0 0 + -t + + O -t +
.
C~,_ + + + ,1,
~ ~ + + + + + t + + + + + + +
H~3 -- + + + + + + + O + + + + + + + + O O O O O -1- 0 + O + O
~ . . _ - -------- -
O I :-
~D ~^ ooooooOOOOOOOO+oooooOoooooo l
~ ~D +
h ,_ ,+ + + -t + + l :::
H ~ O + O O O O O O O -1- 0 + O + + O O O O O + O + O + O O l ..
~!
-- + + ~ , .
U~ + + + + + + + + + + + + + + + ,1, + + + ~ . :
~_ + + + + + + + + + t + + + + + + + + + + + + + + + +
~1 U + + + + + + + + -t + + + + + + + + + O + + + + + + + +
E-l
H l . .... : -
H ~ ~P ~ I :
E~ "~_ + +++ + + I ,'.
C.) ~/ + + + + + + + O + + + + + + + O O + O O + O + O O O O
'¢ ~ ~ . ..... .
~ P~;-+ + + + + + + + + + + + + + + + ,~, + + I :
C~ ~_+ + + + + + + + + + + + + + + + + + + + + + + + + + ~ , .
~;z; E~+++++++++++++++++++++++++++ I .- ' ''.'.:
1:'1 _ I '., .:
H . I .. :
E-l ~^ + +
Z .~ + + + + + + + + + + + + + + + + + + + + + + ~ .. .
~_ + + + + ,~ + + + + + ~ + + + + + + ++ + + + + + + I '":
C~ + + + + + + + ~ + + + + + + + + + + O O + + + + + + + I ; ,
_ ~ ++
U~l + + + + + + + + + +
. ~ + + + + + + + + + + + + + + + t
++++++++++++++++++00++++0++ ~ '
u~ m bq
5~ U~ ~ + U~ ~ I :;' .
o m ~ m ~ m ~ m ~ m l .;
H
,':
U ~ ~ ,~
P; _ _ _ I ,_ ~_ U ~ ~ I
u ~ u u m ~u
~ ~ ~ m ~ --
m m m c~ m ~ I I I z s~ u s~
c)~uuouu~um~ )uu~ rumom~u~Ln
~C .,1 ~1 ~ U ~i ~ U U U U U U O U U U U U U C.~ U U U U ~ U U U U I ,.: : -
~ - ~
~ l :
E~ ~
- 21 - -
, . , ... . . ,, . -~`:
. . ~
~ 7~
i - '.,
ooooo+++~+-+-+-+-t-+oo-~+oo++oo+
~oô ++ + + + : .
~ ++++ ++++++ ++ ++ + ~: .
U~ o o o o + + + + + + ~ + + + + o o + + + o + + + o + . .
+ : .
¢~ oo+o+++++-+-+++-+-+-+++-++t++++
~^ oooo+++ooooo+o+ooo+$~o++o++
. . I
H ~ 1~ O O O O O + O O O O + + O -1' 0 0 0 0 0 0 0 0 -¦- O O O
H___ ~
¢ h ~ + +
~ ~ OOC~OO++OO++OO+OOO+OOO++OOO
~ . ___ .,
H~ ~ + + _ + _ + + _ _ _ _ + + + +
~ ~ +o.~+++ ++ + -+++o+oo---t+o-
~ _
H P ~
H ~_ + _j_ + + + +
¢ ~1 OOOOO++++++++++OOO+OO+-1-00+
,.:1 . + ++++++ +++++ +++ +++
¢,., P;~ + + + + + + + + + + + + + + + + + + + + +
C~ ~ + +++++++++++++ +++++++++
~ E~ +O++++++++++++++o+++++++++
H
7 ++++ ++ + ~++++
~_, +++++++++++++ +++++++++
+ + + + + + + + + + + ~r + + + O + + + + + + + + -1-
_ _
t~,î + + + + + + + + + :'
X O O + + + _ + + _ _ + + + O o + + + + +
~ I~ 4 .
O + + + +
H ¢ ¢ a~ ~ ¢ ¢ ¢ ¢ ¢ ¢ ¢ 1:4 ¢ ¢ ~1 ¢ ~ ¢ I:q ¢ ¢ ¢ ¢ ¢ ¢ ¢
:
.
~I ~ ~ ~ ~ r C`J 1:`1 C`l (~ ~1
P~ ~ ~1 ~ .-1 r~
Ll C~ ) p ~ I
I I d~ X p~
~ Lr~ n U~ ~ C~)
~ ~ o ~ ~ ~
. -
¢ ,1 ~ C~ J r~ 1
_, ~ ~ ~ ~ ~ ~ ~ J
D
,~ c~ . C~ ~ ~ ~ ~ ~ r~l r~l r~
--22--
: :
,
~ ~ '~
.~ :. .
--23--
. .. .,, ~ '.'
1065B7~ ~
~0 ++t+~E+ :"
~3co ~ +o~+:1:
P ~11` 0000 + _1_
~1 __ _ ' I 'i
H j
C~ 3~ +OO+++
~ ~ ~ 1~ +~++++
O- +~+~ ~'
+~
'.
__ H _
~ 00 ~ ~
¢ C~
a) ,~ î :~
C~
-23a-
- -, ~ . ... .. .
1~6S1~73
_ ~,, I ; .,
~,, '-I ',' , ",
~ ô , ,.
P.~ ++ + +o ++ ++ + +__+_~,..+..~ . .
~ ++++ ~++*++~++++ ! :
~ .. ~
~ ~ + o o ~ + o o o o o + + , . .
~ ~ O O O O + + +
¢ h ~ + + I +
<~ ~ . +++++O++O+
H `\X ~\ 3 u~ + + + + + + + ++ + + + +
~ ~_~/ ~ ~ - I `
~ ~
H P~ + + + + + + + + + + + +
:
~o + ++ + + ++ ++ + + ++ + + + 1' '''"
.
:~ +++++.+._+..+...++++
~î ++ + + + + + ++ + + + + ++ I " , ' ~.
~ '." .
~$ ~ Pl ~ S ~ :1; ~ X P:l ~ ~ X ~ -
C`l
¢ ¢
~q c~ ~ ~1 1 ~ ~ I h
0 ~
~ C~
L) I ~I P:l X ^ ~
E~ Lrl c~
. I
--24-- :
. .
- - - :
++t+++++++++++t+
O OOt++++++++++++-+~+
¢`- +++++++++++++++-1~ +
.
A o o o o + + o + + + -1- + + +
~1 A
H ~ 00~0+00+0++000
H . _ . _
H ~ ~ 0+++00++++000+
¢ ¢ a U~ + + + + + + + ~ + + + +
H ~ O+++++++++++++
_ _
h ~ + ++ t+ ++ + + ++ + + + + + + +
. _
~_ +++++++++++++++++++++++
. _
_ ~ +++++++++++++++++++ :,-
U~
$~$~$~$~$~$~$~$~X~$~q .
c, O ~ a a a a a a c~
$~$~$~
~~ $ $ $ $ P~ $ $
~ ' 1~ l~ a c~
:~ ~1 ~ ~ ~ rl I I I I I I I
~ ~ ~ ~ p~ ,~ c~l c~ ~ c`J
a ~ ~ ~, o ~ ,c ~ ~ ~ ~ ~ ~ ,_
¢ ,~ ¢ ~
U~ ~ $rl~U~ p~I_______
~ o C~ . ~ $ ~I ~ ~ ~ I I I ' I ' '
_I ~ o ~ C~ C~
E~ u~ I ' ' ' ~ ,
--25--
:~
- ~31f;S873
_ _ ~ :'.. : '
~ '+++++++o :.
. ~C ~,,
~_ + + ++ -+~ ++ ++ + +
_ ......
~,~ + + + ,. + + + o ''~" '
~ ,.
V~ ,.. ....
~X oo o + ++ ,. + + ;:, '
. __ ,.. ~,,.`
,.....
~ ~, o o o + o o o o ''--.` :` `
r l P _ . :~
1~ 'J~ ~ ++ o + + + ++ o o ~ ~
.~ ~ Y ~ ~ ~
+++++++-~ ,':,
~_ _ ":
E~ ~ t + ++ t ++ + ++ +
E~- I `'"
C~ ++++++++++++ ';
---I ,,;.
~J_ ''~
X- ++++++++++++ '~
::~
.~ ~.3+.
.~ ~ C ,
-I
XU~ 00 ~'
E~ ~ ~ a ~ ~ ~ R s~ `
'
-26-
.. . .. ~ . , ....... .. , . . ::
, ," ,- , , , ~ .
1973
_ ~ o o + + o
~ H O O + O O
H~1/~ ~ H -- O O + O O ¦ ;
~ + + + ~+ ~- ~'
~`_ +++~++++++ ~ '
~ 3 ~ ~, 3 ~
~ X~
,.-:.
~ ~ X ~ C~ .. .,- .
~ ~ $ ~ ~ ~
-27-
_ ~ ;'
~ ;'
~0 + t t t + t + :.
+ + t ~+ + + +
X~ ++ $ -++ ~ + + O '."':'''~'"
. _ __ ''',','
~1 ~ ~ + + + + + O O ; ''
z ~ "~ 3 ~
. ++++++++++
~,~++++++++++++ ~' .,'
X I + + + + + ++ +
_ '" '''
¢ ~ ~ 0
a~ X~y ~ , ~q o
E~ OQ C~
~28-
5~
Table B
ACTIVITY AGAINST PHYCOMXCETES
N
,N ~ R1
CH2 ~ \J
R2
Rl 2 Abs.r. Bas.m. Mort. Rhi.
2,4-(c1)2 4-C1 ~ -~+ ~ .1+
4-Br 2-C1 ~ + + t-~
4-Br 4-Br +++ ++ -~+ -~+
4-CH3 4-Cl ++ + + +
2,4-(Cl)2 4-Br +++ ~ -~ +-~
4-Cl 4-Br +++ ++ -~+ -~
2-C1 4-Br +~ -~ + ++
4-Br 4-CH ++ ++ + ++
4-C1 4-F 3 ++ ++ + +
4-Br 4-F ++
~N
~;R
,~30-CH
R2
Rl 2 Iso~er Abs.r. Bas.m. Mort. Rhi.
4-C1 4-C1 B lll + + +
4-Cl 4-F cis ++ + + +
4-C1 2-CH3 A ~+ ++ + +
4-C1 2,4-(C1)2 B +++ +-~ +~ +
2,4-(C1)2 2-CH3 A t + + + -:
214-(C1)2 4-C1 trans ++ + +~ + -
2,4-(Cl)2 2-CH3,4-ClA + B ++ ++ + + -
4-Cl 2~6-~Cl)2 A ++ + + +
2,4-(C1)2 2-CH3 A ++ + ~ + +
2,4-(C1)2 4-CH3 A + ++ + +
2,4-(C1)2 4-OCH3 A -~+ ++ ~ +
2,4-(C1)2 4-C1 cis ++ ++ + +
2,4-(C1)2 4-Br A ++-~ ++ ++ ++
2,4-(C1)2 H A ++ ++ + +
2,4-(C1)2 3,4-(C1)2 A 111 lll + ~+
2,4-(C1)2 3-Cl A ++ lll +t ++ : -
2,4-(C1)2 2-C1 A +++ ++ + +
2,4-(C1)2 2-Br cis ++ ++
~ "
: - :
-29-
'':
-: -- . - . . - '- :'- ' . . ''~' . , ,, ~ - .'; :~,, ' . . ' -
7~
,
Table C BACTERIOSTATIC AND BACTERIOCIDAL _ACTIVITY
The table summarizes the activity against the gram-positive bacteria, ~ -
- N
h~ 1 ,.. ..
CH2- ~ ~ J
~ ~0
R
.
R R bacteriostatlc activity bacteriocidal activity ~ .
1 .~ _ _ ,
.. E.ins. Staph. Strept. E.ins. Staph. Strept.
:-
4-Cl 4-Cl ++ +~ ++ ~+ ++ ++ :~
4-Cl H ++ ++ +++ . ++ + +t+
4-Cl 2,4-(C1)2 ~ ++ +~+ -t+ ++ m
4-Br 4-Cl 111 111 +-~+ Il~ + 111
4-Br 2,4-(Cl) 2 151 + t I I +++ + +++
2,4-(C1)2 H ++ O ++ ++ O ++ ..
4-OCH3 4-Cl ++ + ++ + + ++ .
H 2,4-(Cl) 2 ++ +* +++ + + ++
2,4-(C~)2 4-Cl +++ ++ 111 ++ + ++
H 4-Cl 111 + 111 + + ++ :
4-Cl 2-Cl +~* ++ 111 +* + -~+
2-Cl 2,4-(C1)2 +-~+ ++ +++ ++ + +++ :~
4-Br 2-Cl 111 + ~+ 111 + ++
2-Cl 4-Cl +-~+ + +t+ +++ + l I l
2 ,4-(C1)2 2,4-(C1)2 +++ ++ +t+ I I I + I ~ I :
4-Br H ++ + 111 ~+ + +++
H 4-Br ~11 O t++ 111 O +-~+
4-CH 2,4-(C132 I I I +++ +++ +++ ++ I I I
4-Br3 4-Br +++ ++ +++ +++ + +++
2,4-(C1)2 2-Cl I I I +++ I I I I I I ~+ +++
4-CH3 4-Cl I I I ++ +t+ +++ + +++
2,4-~C1)2 4-Br +++ ++ +++ ++ + ++
4-Cl 4-Br +++ ++ +-~+ +t+ ++ ++-~ ~ .,
4-CH 4-Br l I I ++ I I I +++ + +++
3-C13 2,4-(C1)2 ++ + +++ ++ + Itl :~
2-Cl 4-Br ++ ++ ++ ++ + ++ : .
4-CH3 2-Cl +++ + +++ +~ + 111
4-Cl 4-CH ~++ + 111 +t + 111
4-Br 4-CH33 I I I ++ ++ ++ + ++ :
4-Cl 4-F + O ++ + O +-~ -.
4-Br 4-F ++ 111 ++ -:
" "'
-30-
~.,
.
- . . : . . .: , . - : . -............... .
~ 1~6~i~7~
__ ~ ~ t+~++~+t++ t,
.~ --I
~ ~ I ''
o __ o+++~+oo~o++o++o+,
d + + + + + + ++ + -+1- + + -1- + + -1- +
H _-- - ¦
~;--' u ~, + + ~+E + ~E + + + + + + + ++ t+ + + +
\J ~ ,U ~
Pq \ o-- JJ ~ + I I I I I ~ I . .
¢~ l'o u u~ +++++ , :.:....
0~ ~3-$ ~ c~ d ~ ++ + ++ ~ ~ O ++l ~ ~+ ~E ++ + + t ++ + I / ~ ~
~ ~ _
\ JJ El ~o d d
~\ o ~ ~ 1:4 ¢ p:l I ,.~,.
P;~ ~ I '~
~:~
p:~ ~ Pd pq ~1 ~1 I Pd ~i t~ C) I --I !
y y y y y y ~ y ~ ~ ol ~ p ~ y
l `,;' '
P~'l l ''
!
'
-31-
: . . - . . . . . : ..
~¢5~73 ::
__ __ . ................... ~
~ + ++ +++++++++++ ++ + ! -:
~ ~ ++++++++++++++++++f+++++++++++f+f+++++++++++++l .
~ . ~ .
.~ ~ ++O-~++++O+++++f+++++oOo-~++O++OI
D Ul
.~ +-+~t++t++++++~++++-f~-+~++++++ t o ++ ++ t + + ++ + I
H
:~ P, ~ ++ +++ + .I
~3 .~ h + + ++ ++ + + + + + * + + +~ +~ + + ++ + +~ ++ + + +~_ + + + ++ + +
H
~) ~,) ~
~ O ~ t++f++t+++O++++t+++++++OO++++o++++l
¢~ ~) _~ . '-.;
H D U~
W f+++++++f++++++++++++++++++f+++++++++++
P$ . ..--.-._- ................................ ~ ~
~$ h
O p~ ~q ¢ ¢ ¢ ¢ ~ 4 ¢ ~ ¢ p~ ¢ ¢ ¢ ¢ + ~ ¢ ¢
H ~ ¢ ~~ .
-1
C~ ~ ~ ~ ~ I
,m,
I$ ~UHml~l l~X~lllz~oh^
1~O C~ C~ ~ U 1~ U C.7 ~ 4 0 ~ U
I '~
~ P~ ~) U C ) ~ U ~) U C~
~ o
E~ c~l I ', ';
~ .
--32--
~ 6~1~73
_~
.~ U~ +t+t++++++++++++++++t+++++++++++++++
." _ . .
',~ u~ o+++++++o-~+o-+~+oo-t+++~-~+-+~++
_ .
~d ~q
,C ++++++++++++++++++-+t+++++O++~-+~t++ :t t++++t
~ .. ... _ _ ',,
H ~
~ h ++++++¦++++~+++++++-~++++t++
C~rl ~ '~ :'
1:~
O++++++t++Ott+++t+OO+t++++t++++
H ~ ......................... __ ..
H ~ +~++++~+++++++++0++~++++++++++ ; ~
~_~ --
4 ~-.: ,, '.
~a ¢ ~ a: ¢ ¢ ¢ ¢ ¢ ~ + F~ ¢ ¢ ~4 + ~ ¢ I:q * ~ + ¢ ~ ¢ ¢ :
H ¢ ¢ ~ ¢ :
.. _ . ._ _ "" ~ '
~ X~ ~ ~
~J ~ - .
,î ~
~; ~ ~ I
$ $ P~ I ~
~ ^
U~h ~ q o$~D I~ I I C.) --1 ~ I $~) :
~ ~ 4 m ~ o ~ ~ ~ U ., u~ c~
_ _ __ . : '
.~~I ~ ~ ~ ~ ~ ~ ~ ~ ~ ~I ~ ~I ~ ~ ~ ~I
~ C~
O~ ~ ~ ~ ~ ~ C~ ^ ^ ^ ^ " ^ '`
-32a- :: .
6~i8~;~
Table C
3 BACTERIOSTATIC AND BACTERIOCIDAL ACTIVITY -~
N
N
R 2--
`;9\ ~-S-CH--
Bacteriostatic activi~TBac~eriocidal activity
Rl R2 Isomer E.ins. Sta~ Strept. E.ins. Stelph. Strept.
2,4-(C1)2 4-Br A + B ~ ++ +-~+ ~ ~ ~ +++
2,4-(C1)2 A + B +~+ ++ _ -~+ + +++
., - ; .
Table C
N
~ 2 .
Rl R2 Isomer Bacteriostaticactivity ¦Bacteril ~c~d~l tivity
-E.ins. Staph. Strept. E.ins. Staph. Strept.
,,.,., . __ , ,.
2,4-(C1)2 2-Cl ++++ +++ IlIl II~ ++ t+~
2,4-(C1)2 2,4-(C1)2 l I I I ~+ I l l I +++ ++ +-~+ .~
2,4-(Cl)2 2,6-(Cl)2 A + B ++~+ lll ++++ 111 -~+ 1~+ ~ -
2,4-(Cl)2 4-OCH A + B ~ + 111 +t+ + ++
2,4-(Cl)2 4-C1 3 ~ ~+ ++++ 1~1 ~ I ~1
2,4-(C1)2 H +~ ++ +++ 0 _
-33-
~- '
.~ ~ +$oo+++~+++++ $~++++++o+++++
0 _ . _. ~
.,~ cn o + o o + oo oc:)o -~ + oo + oo oo ~ + t I ~ `
~ _ .......... . - 1l '' . .
~ .~ +++O+++~_~,+++++++ + ++++I j ~; '"'
H ... ... _ _ _
H l a) ~ ; .;
H ¢ ~1 JJ + O + + + + + + + + -~ + + + + + ~ + + + + I ::
H \ ___ ------- ------- - -------- I ; ~. : ~.~ ~.cp, ~++o++++oo ++o +++ o+++
¢ L~ a~ ~ j ~,
1~ ~i ++ + ++ + -1_ + + + + + + +~ + + + + + + ~ . .
~ ~1
O ++++++++++++++++++++++
~ ¢¢¢¢¢¢¢¢¢¢¢¢¢¢¢¢~¢¢¢¢¢ !
.. . _ .. I . .;
~ ~ /$ ~ $ $~
_ . - '-- 1 ~"''.
~ ~ $ ~ ~ $ `D h ~ ~ $ ~
~ ¢ ~ ~ ~ I $~ ~ 7 ~
~_I I ~ $ ~ 'I I O ~ $ ~ 1:1 C.) O I I 1
-34
-, . . . - .. ` ,.. ,-`- ... . :. ... . `~ .
3.~16
.
~ .. ::
.~ h i -t ~ ~ + + o +
.~
. ~ .
,, ~ +++ :
V C ~ + + O O O o +
V ~q
3 ++ ++ ~+ + o ++ + +~
~ , ..
H .
H
¢ .~ ~ . .,_ _ ., ' '
H V
.V ~ .,' ' . .
a:l ~ u : :: : _ _ .
~ .0 U~ _ _ __ -OOoo_ _ ~''' ' ' ~
H V ~q
o~ ,d +++ +++++ :
,~ ,
,: ." . -
4 ;'''
O + + + + ~ + ~rl +
.,1 ~C ~ ~ ¢ ~ ¢ ¢ ~ :
~ ~ .
~ ~ 0~
~D 1~ 00 C`l C`J C`l
X
~:: 5 ~
~ ~ ~ ~ ~ ~ ~ ~D ~`
X $ ~ ~ ~ X ~
~9 ~ ~U~ ~ ~1
¢ _~)~ ~C~î
V ~
Ui O ~ :~
~_i U
rO ~~ ~ ~;t ~ ~ ~ ~ ~t
~i
E~ u~ ~ C`l C~
_
-34a-
106~B73
BACTERIOSTATIC AND BACTERIOCIDAL ACTIVITY
: - .
Table C
6 ~ ~ Cl
CH2- ~ Cl
Alkyl-O-CH2 , ~: .
Bacteriostatlc activity Bacterlocidal activity
Alkyl isomer E.ins. Staph. Strept. E ins. Sta h. Stre t.
.... _.................... . P P
CH3 cis + O O + O O
C2H5 trans ++ + ~+ ~ O +
nC3H7 cis ~ ++ + + ++ O O
nC4Hg A + B +++ ++ +-~+ + O ~
nC5Hll cis +++ +++ ~11 +++ O ++ --
nC6H13 cis 111 ++ ++ ++ + ++ ;
nC7H15 cis lll lll lll lll + ++
nC8H17 cis _ _ ++ +++
Table C
-:
7 ~ ~ Cl
N \ ~
CH2 _ _ - ~ C~ `
O O ::
Aryl-CH2~0~CH2
: . .
ArylisomerBacteriostatic activity Bacteriocidal activity
E.ins. Staph. Strept. E.ins. Staph. Strept. -
( 6 5) 6 4 cis +++ lll +++ +++ + +-t+
( 6 5) 6 4 trans lll ++ lll +-~+ ++ +++
4-Br-C6H cis lll ++ lll +++ +
2,4-(Cl)2-C6H3 cis +++ 111 111 ++ + ++
2,4-(Cl)2-C6H3 trans _ _ +~
:' ' :.
. . .
5~3
BACTERIOSTATIC AND BACTERIOCIDAL ACTIVITY
Table C
~ ~ Cl
7 ~ :: -
CH2 ~ ~ ~ Cl
Aryl-CH I
Aryl Bacteriostatic activity Bacteriocidal activity
E.ins. Sta h. Stre t. E.ins Sta h Stre t ~ .
_ .. . P . P . _ P P ~ .-'
C6~15 +++ ++ ++ ~ ~ ++ 4-Cl-C6H~ -H~ ++ ++ +++ +t ++
4-F-C6H +++ ++ ++ ++ + ++
4-CH -C H 111 ++ +++ +++ ++ +++
4-Br-C H +++ ++ I I I +++ ++ -~++ .. .
3 6 4 +++ + +++ 111 + +++
( 6 5) 6 4 ++ . ++
1~)658~ 3
In view o~ the aiorementionotl antif~nga1 and antibacterial
activities this invention provides valuable compositions comprising
the subject 1, 3-dioxolan-Z-ylmethyl imidazoles ( I ) or the acid
addition ~alts thereof as the active ingredient in a solvent or a
solid, semi-solid or liquid diluent or carrier, and, in addition, it
provides an e~fective method of co1nbatting fungus o~ bacterial ~
growth by use o an effective anti-fungal or anti-bacterial amount _
of such ketals ( I ) or salts thereofO The subject con~pound.s can .
be used in suitable solvents or diluents, in the Lorm of emulfiions,
suspensions, dispersions or ointments, on suitable solid or semi-'
801i~1 carrier substance6, in ordinar~r or synthetic soaps, detergents
or dispersion media, if desired, together with other compounds .
having arachnicidal, insecticidal, ovicidal, f~mgicidal and/or
bactericidal effects, or togetller with inactive additives.
Solid carrier sul)stances which are suitable for the
prcparation o compositions in powder form include various inert, ~.
porous and pulverous distributing agents of inorga.nic or organic
nature, .such as, for example, tricalcium phosphate, calcium
carbonate, in the orm of prepared cllalk or grc~und limestone, ~
kaolin, bole, bentonitc, talcum,.kieselguhr and boric acid.; powde~ed _
cork, sawdust, and other ~ine pulverous materials of vegetable origin
are also suitable carrier substances. -
~-
The active ingredient is mixed with these carrier ~ .. .
substances, for example, by being ground therewith; alternatively, ~.
the inert carrier substance is inlpregnated with a solution of the
active component in a readily volatile solvent and th;e solvent is j~
thereater eliminated by heating or by filtering with suction at _ :
reduced pressu:re. By add.ing wetting and/or dispersing agents,
such pulverous preparations can also be made read.ily wettable
with water, so that suspen6ions are obtained.
r,
,
.~ .
_37- . I
t'~
`
73 ~-
Inert solvents used for thc production of liqui~J~-
preparations should preferably not be readily infiammable
and should be aa far as possible odorless and as Iar as possible
non-toxic to warm-~ooded animals or plants in the relevant
surroundings, SolYents suitable for this purpose are hi~h-boiling
oils, for example, of vegetable o~igin, and lower~boiling 901vents
with a flash point of at least 30C., such as, for examplc, polyethylene
- ~lycols, isopropanol, dimethylsulIoxi(le, hydrogenated napllthalenes
and alkylated nal)hthalenes. It is, o~ course also possible to use
mixtures of sol~rents. Solutions can be prepared in the usual way,
if neccssary, with assistance of solution promotors~ Other liquid -~
forms which can be used consis1: of emulsions or suspensions of the
acti~re compound in water or suita~le inert solvents, or also
concentrates for preparing such emulsions, which can be directly
adjusted to the re~uired concentration. For this purpose, the active
ingredient is, for example, mixed with a dispersing or cmulsifying
agent, The active.component can also be dissolved or disperscd in a
suitable inert solvent and mixed simultaneously or subsequently ~vith
a dispersing or emulsifying agent,
- It is also possible to use s~mi-`solid carrier substances
of a cream ointment, paste or waxlike naturc, into which the
active component can be incorporated, if nccessary, Witll the aid
of solution promotors and/or emulsifiers. Vaseline and other
cream bases are examples of semi-solid carrier substances.
Furthermore, it is possible or the active component
to l)e used in the form of aerosols. For this purpose, the active
3 8
,
- ~' ' . ' .
5~3
component is dissolved or dispersed, if necessary, with the aid of
suitable inert solvents as carrier liquids, such as difluorodichloro-
methane, which at atmospheric pressure boils at a temperature
lower than room temperature, or in other volatile solvents. In
this way, solutions under pressure are obtained which, when sprayed,
yield aerosols which are particularlysuitable for controlling or
combatting fungi and bacteria, e.g., in closed chambers and s~orage
rooms, and for application to vegetation Eor eradicating or for
preventing infections by fungi or bacteria.
The sub~ect compounds and compositions thereof can be
applied by conventional methods. For example, a fungus or bacterial
growth or a material to be treated or to be protected against attack -~
by fungus or bacterium can be treated with the subject compounds and
the compositions thereof by dusting, sprinkling, spraying, brushing,
dipping, smearing, impregnating or other suitable means.
., ,, .~, .
When the subject compounds are employed in combination
with suitable carriers, e.g., in solution, suspension, dust, powder,
ointment, emulsion, and the like forms, a high activity over a very
high range of dilution is observed. For example, concentrations of
the active ingredient ranging from 0.1 - 10 percent by weight, based `~
on the weight of composition employed, have been found effective in
combatting fungi or bacteria. Of course, higher concentrations may
also be employed as warranted by the particular situation.
The following examples are intended to illustrate, but
not to limit, the scope of the present invention. Unless otherwise
stated, all parts are by weight.
-39-
::
''~. ' " ,
- ~ . . .
~6S~'73
Example I
A mixture of 11.7 parts of 2-bromo-4'-chloroacetophenone,
9 parts of 1-(p-chlorophenyl)-1,2-ethanediol, 0.5 parts of p-toluene-
sulfonic acid and 80 parts of benzene is stirred and refluxed Eor 2
days with water-separator. The reaction mixture is cooled and washed
successivelytwice with a sodium hydrogen carbonate solution and once
with water. The organic phase is dried and evaporated. The residue
is triturated in petroleum ether and cooled on ice. The precipltated
product is Eiltered off, crystallized from methanol, stirred in
acetonitrile while cooling on ice, filtered off again and washed
once more with acetonitrile, yielding 2-(bromomethyl)-2,4-bis(p-
chlorophenyl)-1,3-dioxolane.
Example II
A mixture of 11.6 parts of 2-bromo-4'-chloroacetophenone,
8.4 parts of ~-(hydroxymethyl)benzylalcohol, 0.1 parts of p-toluene
sulfonic acid, 210 parts of benzene and 40 parts of ethanol is
stirred and refluxed for 24 hours. The reaction mix~ure is evaporated
and the residue is triturated in methanol. The product is filtered
off and crystallized from methanol, yielding 2-(bromomethyl)-2-(p-
chlorophenyl)-4-phenyl-1,3-dioxolane; m.p. 60C.
-40-
~5t~73
Example III
A mixture of 11.6 parts of 2-bromo-4~-chloroacetophenone,
12.4 parts of 1-(2,4-dichlorophenyl)-1,2-ethanediol, 0.1 parts of ~ .
p-toluenesulfonic acid, 80 parts of n-butanol and 160 parts of .
benzene iS stirred and refluxed for 24 hours With water-Separator.
The solvent is removed in vacuo and the residue is triturated in
methanol. The precipitated product is filtered oEf and crystallized
from petroleum ether, yielding 2-(bromomethyl)-2-(p-chlorophenyl)- :~
4-(2,4-dichlorophenyl)-1~3-dioxolane; m.p. 82.7C.
.. . . . . .
Example IV
Following the procedure of Example III and using equi-
valent amounts of the appropriate starting materials the following
dioxolanes are obtained eventually after further purification by
one of the following procedures:
a) by column-chromatography over silica gel uSing tri-
chloromethane as eluent; or .
b) by stirring the product with silica gel in trichloro- ~ ~
methane, filtering off the silica gel and evaporating , ~ ,
the solvent.
~
BrCH2 ~ R6 ~ ; .
R7' :
,-,.~ ' .
-41- .
': '.' . , - '. ' ~:
,. - : . .
1065873 ~ ~
R~ R7Melting Point PuriIicati~n
procedur~_
4-Br 4-C1 101. 3C
4-Br 2, 4-(Cl,~2 99. 9C
4-OCH3 4-Cl llS. 6C
4-Cl ~3 9C
4-CH3 Z. 4 (Cl)z 89 9C
4-Br 4-Br 96. 8^C
4-CH3 4-C1 122 C
4-CH3 4-Br ` 118,6^C
4-CH3 2-Cl
2, 4_tCl)2 ~ a
2, 4_(C1)2 ~ a
2, 4-(C1)2 4-Cl ~ a
4-(:;1 2-CI
2-Cl 2,4-(Cl)2 - b
4-Br 2-Cl - b
2-C1 4-C;l - . b
2,4-(C1~2 2,4-(Gl)2 - b
4-Br - - 70G b
- 4-Br 71. 3C b
2, 4_(C1)2 2-Cl - b
Z, 4_(C1)2 4-Br _ - b
4-C1 4-Br 80. 5,C b
3-Cl Z 4-tCl)z - b
2-C1 4-Br , - b
4-C1 4-C~3 - b
4-Br 4-CH3 - b
4-C1 4-F - b
4-Br 4-F - b
.. . .
--42--
.
7~
Example V
To a stirred and refluxing Grignard-complex7 previously
prepared starting from 98 parts of 1-~chloromethyl)-2,4-dichloro-
benzene and 14 parts of magnesium in 70 parts of l,l'-oxybisethane,
is added dropwise a solution of 46.5 parts of 2-(chloromethyl)oxirane
in 350 parts of l,l'-oxybisethane. Upon completion, stlrring at reElux
temperature is continued overnight. The reaction mixture is cooled
in an ice-bath and decomposed by dropwise addition of 120 parts of
a concentrated hydrochloric acid solution. The whole ls poured onto
water and the layers are separated. The orKanic phase is washed
three times with water. The aqueous phase is extracted with
l,l'-oxybisethane. The combined organic phases-are dried, filtered
and evaporated. The residue is distilled, yielding 2,4-dichloro-~-
(chloromethyl)benzenepropanol; bp. 130C at 0.04 mm. pressure,
.,,.~ .,,
Example VI ;
Following the procedure of Example V and using equi-
valent amounts ofthe appropriate starting materials, the following
compounds are prepared:
OH
~ CH2-CH2-1H-CH2Cl
R
., :, "
R boiling point
2-C1 118C. at 0.01 mm. pressure
2,6-(Cl)2 136C. at 0.2 mm. pressure
4-OCH3 140C. at 0.2 mm. pressure
4-C1 130-135C. at 0.3 mm. pressure
-43-
~)6~ 3
Example VII
A solution of 87 parts of 2,4-dichloro-~-(chloromethyl)-
benzenepropanol in 144 parts of concentrated sodium hydroxide solution -~
and 350 parts of 2,2'-oxybispropane is stirred overnight at room tem-
perature. The product is extracted with 2,2'-oxybispropane. The
extract is washed with water, dried, filtered al~d evaporated. The
oily residue is distilled yielding [2-(2,4-dichlorophenyl)ethyl]oxirane~
bp. 90-98C at 0.01 mm. pressure.
Example VIII
Following the procedure of Example VII and using equi-
valentamounts of the appropriate starting materials, the following
oxirane derivatives are prepared:
R ~ CH2-CH2 / ~
R boiling point
2-C1 66-70C at 0.01 mm. pressure
2~6-(cl)2 85-89C. at 0.01 mm. pressure
4-OCH3 80-90C. at 0.05 mm. pressure
4-C1 106-115C. at 0.03 mm. pressure
-44-
- : ,: -- . . .'.. :
-- - . - ' -. : :
Example IX ~ -
: .
To a stirred and refluxing Grigand-complex, previously
prepared starting from 89 parts of 4-Cchloromethyl)-l,l'-biphenyl
and lZ.5 parts of magnesium in 350 parts of l,l'-oxybisethane, is
added dropwise a solution of 60 parts of 3-bromo-1-propene in 180
parts of tetrahydrofuran. Upon completion, stirring is contin~ted Eor
2.50 hours at reflux temperature. The reaction mixture is cooled and
poured onto water. The layers are separated and the aqueous phase
is extracted with l,l'-oxybisethane. The combined organic phases are
washed with water, dried, filtered and evapora~ed. The residue is
filtered and the filtrate ls evaporated, yielding 60 parts of 4-(3-
butenyl)-l,l'-biphenyl as a residue.
To a stirred mixture of 88 parts of 3-chlorobenzene-
peroxoic acid and 650 parts of dichloromethane are added dropwise
60 parts of 4-(3-butenyl)-1,1'-biphenyl. Upon completion, stirring
is continued over week-end at room temperature. Then there are
added dropwise 50 parts of a potassium carbonate solution.
The organic phase is separated, washed with a sodium ~isulfite -~
solution and with water, dried, filtered and evaporated, yielding 63.5
parts (70.87%) of [2-([l,l'-biphenyl]-4-yl)ethyl]oxirane as an oily
residue.
Example X
To a stirred mixture of 86 parts of 3-chloroben~eneperoxoic
acid and 650 parts of dichloromethane are added dropwise (;lowly)
53 parts of l-fluoro-4-(2-propenyl)benzene. Upon completion, stirring
is continued overnight at room temperature. Then there are added drop-
wise 92 parts of a potassium carbonate solution and the layers are
separated. The organic phase is washed with a sodium bisulfite solution,
dried, filtered and evaporated, yielding 58.4 parts (98%) of 2-(4-fluoro-
phenylmethyl)oxirane as an oily residue.
~45~
, . . .. : . . . . - . : :
- . : . - . . . : .
~S~7~
Example XI
To a stirred mixture oE 44.5 parts of 4-chloro-1-naphthalenol
; and 115 parts of 2-(chloromethyl~oxirane are added portionwise 17.1 parts
oE potassium hydroxide (exothermic reaction). When the exothermic
reaction is ceased, the whole is heated to reflux and stirred atreflux
temperature for 2 hours. Water i5 added and the whole is extracted twice
with trichloromethane. The combined extracts are washed three times with
water, dried and evaporatedO The residue is distllled, yielding 45.3 parts
of 2-[(4-chloro-1-naphthalenyloxy)methyl]oxirane; bp. 150-151C at 0.2 mm.
pressure.
Example XII
Toa stirred solution of 139 parts of 2-nitrophenol and 138 parts
of potassium carbonate in 640 parts of 2-propanone are added dropwise 215
parts of 2-(chloromethyl)oxirane. Upon completion, stirring is continued
for 2 days at reflux. The formed precipitate is filtered off and the
filter-cake is washed with 2-propanone. The filtrate is evaporated. The
residue is crystallized from a mixture of 2,2'-oxybispropane and petroleum-
ether (1:1 by volume). The product is filtered off and dried, yiélding 38
parts (20%) of 2-(2-nitrophenoxymethyl)oxirane; mp. 56C.
Example XIII
Following the procedure of Example XII and using an equivalent
amount of an appropriately substituted phenol or naphthalenol in place of
the 2-nitrophenol used therein, the following 2-aryloxy-methyloxiranes
are obtained: `~
2-[(2-chloro-5-methylphenoxy)methyl]oxirane; bp. 115C at 0.05 mm
pressure;
2-(3,4,5-trichlorophenoxymethyl)oxirane as an oily residue;
2-(3-chloro-[1,1'-biphenyl]-4-yloxymethyl)oxirane as a residue; and
2-[(1,6-dibromo-2-naphthalenyloxy)methyl]oxirane as a solid residue. ,
,,
-46-
- . . -: ........ . . ............ . , ,,~,
. . .
Example XIV
To a stirred solu~ion of 38 parts of 2-(2-nitrophenoxymethyl)-
oxirane in 10 parts of ethanedioic acid and 300 parts of 1,4-dioxane -
are added 100 parts of water. The whole is stirred and refluxed for
2 days. The reaction mixture is evaporated and the residue is crys- .
tallized from a mixture of 2,2'-oxybispropane and petroleumether.
The product is fil~ered off and recrystalli~ed from 2~2'-oxybispropane,
yielding 29.5 parts (13%) of 3-(2-nitrophenoxy)-1,2-propanediol;
m.p. 96C.
Example XV -~
Following the procedure of Example XIV and using an equi-
valent amount oE an appropriately substituted oxirane in place of the -
2-[(2-nitrophenoxy)methyl]oxirane used therein, the following diols are
obtained:
3-(4-chloro-~-naphthalenyloxy)-1,2-propanediol; mp. 120C;
3-(2-chloro-5-methylphenoxy)-192-propanediol; mp. 59C;
3-[4-(phenylmethyl)phenoxy]-1,2-propanediol; mp. 70C,
3-(3,4,5-trichlorophenoxy)-1,2-propanediol; mp. 64C;
3-(3-Chloro-[l,l'-biphenyl]-4-yloxy)-1,2-propanediol; mp. 60C;
3-(1,6-dibromo-2-naphthalenyloxy)-1,2-propanediol; mp. 139C;
3-(4-bromophenyl)-1,2-propanediol; mp. 60.6C;
3-(4-fluorophenyl)-1,2-propanediol; bp. 125C at 0.05 mm pressure;
and
4-([1,1'-biphenyl¦-4-yl)-1,2-butanediol; mp. 125.9C.
-47-
:
S~ 3
1-[2-(2,4-dichlorophenyl)ethyl]ethanediol; mp. 83.2C;
1-[2-(2-chlorophenyl)ethyl~ethanediol; mp. 64.1C;
4-(2,6-dichlorophenyl)-1,2-butanediol; mp. 111.7C; and
1-[2-(4-chlorophenyl)ethyl]ethanediol; bp. 150C at 0.02 mm. pressure.
Example XVI
To a stirred solution of 12 parts of 2-[2-(4-methoxyphenyl)-
ethyl]oxirane in 1.8 parts of sulfuric acid and 160 parts of 2-propanone
are added 100 parts of water. The whole is stirred for 2 days at room
temperature. The reaction ~ixture is stirred with a sodium bicarbonate
solution and the product is extracted with trichloromethane. The extract
is dried, filtered and evaporated, yielding 1-[2-(4-methoxyphenyl)ethyl]-
1,2-ethanediol as a residue.
Example XVII
To a stirred and hot (50C) solution of 64 parts of 1-(3-
bromo-4-methylphenyl)-1-ethanone in 160 parts of l-butanol are
added dropwise, during a 1 hour-period, 48 parts of bromine
without external heating. After sitrring for 1 hour at room temperature
there are added successively 21.7 parts of 1,2-ethanediol, 6 parts
of 4-methylbenzenesulfonic acid and 720 parts of benzene and the whole
- 20 is stirred and refluxed overnight with water-separator. The reaction
mixture is evaporated and the residue is taken up in 2,2'-oxybispropane.
The resulting solution is washed successively once with a diluted sodium
hydroxide solution and three times with water, dried, filtered and
evaporated. The residue is distilled, yielding 57 parts ~(57~) of ,
2-(bromomethyl)-2-(3-bromo-4-methylphenyl)-1,3-dioxolane; ;
bp. 126-130C at ~.1 mm pressure.
-48- -
~0~5~373 i
Example XVIII
Following the procedure oE Example XVII and using an equi-
valent amount of an appropriate l-aryl-l-ethanone in place of the
1-(3-bromo-4-methylphenyl)-1-ethanone used therein the following
2-aryl-2-(bromomethyl)-1,3-dioxolanes are prepared:
2-(bromomethyl)-2-(4-chloro-2-methylphenyl)-1,3-dloxolane;
': ' ' , '
2-(bromomethyl)-2-(3,5-dichlorophenyl)-1,3-dioxolane; mp. 5~C; ~
'' :
2-(bromomethyl)-2-(2,3-dichlorophenyl)-1,3-dioxolane; bp. 135-
137C at 0.1 mm. pressure;
2-(bromomethyl)-2-(2,4,5-trichlorophenyl)-1,3-dioxolane; bp.
146-147C at 0.3 mm. pressure; and
.; ~.
2-(bromomethyl)-2-(2-chloro-4-methoxyphenyl)-1,3-dioxolane;
mp. 53C.
Example XIX ~;
To a stirred solution of 112 parts of 4-(2-bromoacetyl)-
benzonitrile in 320 parts of butanol are added 5 parts of 4-methyl-
benzenesulfonic acid and 360 parts of benzene. Then there are added
dropwise 46.5 parts of 1,2 ethanediol. Upon completion, stirring is
continued for 4 hours at reflux. The reaction mixture is evaporated.
The oily residue is crystallized from 2,2'-oxybispropane. The product
is filtered off and recrystallized from methanol, yielding 95.12
parts of 4-[2-(bromomethyl)-1,3-dioxolan-2-yl]benzonitrile; mp.
92.4C.
. '
: ' .,
-49-
- : .. ~ . -, . : .
873
Example XX
Following the procedure of Example XIX and using an
equivalent amount of an appropriate l-aryl-2-bromo-1-ethanone
in place of the 4-(2-bromoacetyl~benzonitrile used therein, the
following 2-aryl-2-(bromomethyl)-1,3-dioxolanes are prepared:
2-~bromomethyl)-2-(2-naphthalenyl)-1,3-dioxolane; mp. 64C;
2-(bromomethyl)-2-(4-bromo-2-methylphenyl)-1,3-dioxolane; mp.
86C;
2-(bromomethyl)-2-(3-bromophenyl)-1,3-dioxolane; mp. 50C; and
2-(bromomethyl)-2-(3-nitrophenyl)-1,3-dioxolane; mp. 88C.
Example XXI
A mixture of 11.7 parts of 2-bromo-4'-chloroacetophenone,
11.9 parts of 1-(4-chloro-o-tolyloxy)-2,3-propanediol, 2.5
. parts of p-toluenesulfonic acid and 240 parts of benzene is
.' stirred and refluxed for 24 hours in a four-necked round-
bottomed flask equipped with a watertrap. The benzene solu-
tion is washed successively with a diluted sodium hydroxide
solution and with water. The solvent is removed in vacuo.
The residue is crystallized from methanol and the less pure
- 20 fraction is recyrstallized from diisopropylether, yielding ~ -
A-2-(bromomethyl)-2-(p-chlorophenyl)-4-(4-chloro-o-tolyloxy- ;~
methyl)-1,3-dioxolane; m.p. 102.5C. The methanol filtrate
is evaporated in vacuo, yielding B-2-(bromomethyl)-2-(p-
chlorophenyl)-4-(4-chloro-o-tolyloxymethyl)-1,3-dioxolane
as a residue. ~
. .
.'~ - ~.
. . . .
-50-
: : -- . : .: . .. : - . . . .
: : :
:
~LO~i~1!3'73
.
Exan~ple XXII .
. ' ~ '
- Following the procedure of Example XXI and u~ing :
equivalent amoun~s of the appropriate ~tarting materiala
the following dioxolanes aro obtained ~ventually ~fter
purification of the products by:
a) column-chromatography over ~ilica gel u~ing
trichloromethane a~ eluent; or
.
b) stirring the product with ~ilica gel in trichloro-
methane, filtering ofl the silica gel and ~va-
porating the ~olve~t.
.
,~0,CHz~
R7
'' ,"~, '.
.
' ::
I~omer ~6 R7 MeltingPurification
Pointprocedure
A . 4-Cl 4-CH3
B 4-Cl 4 CH3 - - .
A 4-Cl 2, 4-(Cl)~ 87-B9C
n 4-Cl 2, 4-(Cl)2
- A 4-Cl 4-F 102~C -
B 4-C1 4 F
A 4-Cl 2~CH3 82~ 2-85(; - ;
,
--51-- : .
~6~ 3
Melting Purification
Isomer R6 R7 Point procedure
B 4-C1 2-CH3
A 4-C1 2-C1 85-88.6C
B 4-C1 2-Cl
A 4-C1 4-OCH3 ~ -
B 4-C1 4-OCH3
A 2,4-(C1)2 4-F
A 2,4-(C1)2 4 3
A 4-C1 4-C1 165C
B 4-C1 4-Cl - a
B 2,4-(C1)2 4-CH3 - b
A 2,4-(Cl)2 3
A 2,4-(C1)2 4-Cl _ _
B 2,4-(C1)2 4-Cl - b
A 2,4-(C1)2 2,4-~Cl~
B 2,4-(C1)2 2,4-(C1)2 - b
A -~ B 4-C1 2,6-(Cl)2
A + B 2,4-(C1)2 2-CH3
'
Example XXIII
A mixture of 11.2 parts of 2,2',4'-~richloroacetophenone,
14.9 parts of 1-(2,4-dichlorophenoxy)-2,3-propanediol, 3 parts of
_-toluenesulfonic acid and 240 parts of benzene is stirred and refluxed
for 20 hours in a four-necked, round-bottomed flask, equipped with a
water-trap. The reaction mixture is washed successively with a
diluted sodium hydroxide solution and twice with water. The solvent
is removed in vacuo. The residue is triturated in methanol for
3 hours. The precipitated product is filtered off and crystallized
from 2-propanol, yielding A-2-(chloromethyl)-4-(2,4-dichloro-
phenoxymethyl)-2-(2,4-dichlorophenyl~-1,3-dioxolane; mp. 92.5C.
-52-
B~3
.
Example XXIV
A mixture of 6 parts of 2-bromo-2',4'-dichloroacetophenone,
6 parts of 3-(4-chloro-o-tolyloxy)-1,2-propanediol, 3 parts of
p-toluenesulfonic acid, 80 parts of n-butanol and 180 parts of benzene
is stirred and refluxed for 24 hours with water-separator. The solvent
is removed in vacuo and the residue is triturated in methanol. The
product is filtered off and crystallized from petroleumether, yielding
A + B 2-(bromomethyl)-4-(4-chloro-2-tolyloxymethyl)-2-(2,4-dichloro-
phenyl)-1,3-dioxolane.
Example XXV
Following the procedure of Example XXIV and using equi-
valent amounts of the appropriate starting materials and the in-
dicated solvent, the following dioxolanes are prepared:
~: ;
BrCH2~'~ ~E6
R -0-CH2 1 1 ;
.
Isomer R6 5 Melting Solvent
R Point
A 2,4-(C1)2 C6H5 97.6C benzene
A 2,4-(C1)2 3,4-(C1)2-C6H3 - benzene
A 2,4-(C1)2 3-Cl-C6H4 - benzene
A 2,4-(C1)2 3,5-(CH3)2,4-Cl-C6H2 115.8C benzene
-53-
- . .
7~
.;
I~omer Po~nt Solvent
__
A 2, 4-(C1)2 2~ 4-(Br)2-C6H3 - bcnzenc
A 2~ 4-(Cl)2 ~-CN-C6H4 _ benzenc
A 2, 4-(Cl) 2 2-CH3-C6~4 _ benzene
~+B 2~ 4-(~::1)2 4-(c6~5)-G6,~r,1~ - bcll~enc
A~B 2, 4-(Cl)z 4 ~C~(CH3)~7 C6H490 C mcthylbenzene
.2, 4-(Cl)2 3_CH3. 4-(~1-C6~3 methylbenzene
A ~,4~;1) 2 3~5~(Cl~2~c6H3 - methylbenzene
~ ~ 2, 4-(C1)2 4 ~!-C(C~I3)37- C6~4 - methylbcnzene
A 2,4-(C1)2 2-naphthalenyl 117.6C benzene ~ :
A 2, 4-~Cl)2 2-F-~6H4 125, 7C benzene : :
A~B 4-CH3 4-Br-C~;H~L 121.1 C benzene
A+B 4-C1 4-Br-C6H4 157. 4LC benzene
A+B 4-Br 4-Br-C6H4 158. 7G benzene ~:
A 2,4-(Cl)2 3-Br C~,H~ 112.7C benzene
A 2, 4-(C1)2 ' ( 3)2 6 3 118, 7C benzene ::
A+B 2, 4-(Cl)z~ 4-(C6H5-cHz)-c6H4 106. 1 C benzene
A+B 4-OCH3 4-Br-C6~I4 11 7C benzene
A _ 4-Br-C;6H4 85.6C ben~er.e .
A+B 2, 4-(Cl)2 4-Cl-1 -naphthalenyl 122. 7C benzene : :
A 2, 3, 4-(C~1)3 4-Br-G6H4 _ methylbenzeneA 2, 4 (C1)2 2-Br, 4-CH3 C~,H3 ~ methylbenzene :.
A +B 2, 4-(Cl)z 1, 6-(Br)2-2-naphtha- - methylbenzene
lenyl
A+B 2-Gl, 4-Br ( ~ 5) 6 4 dimethylbenzene ;~
A+B 3, 4, 5-(C1)3 4-(C6H5)-C6H4 - dimethylbenzene
A 2~ 4-(~1)2 2-CN-C6H~ _ dimethylbenzene
.A 2, 4-(C1)2 4-(nC4H9-OOC)-Ç6H4 - dimethylbcnzene .
--54-- . , .
, . : - . . .:
:
~065~373 ~
Example XX~rI ` ~^
A rnixturc of 13.6 parts of 2-bromo-1-(2,4-dichlorophenyl)-
I-ethanonc, 12 parts of 3-(2,5-climct~ylpl~cnoxy)-1,2-propanc-
diol, 3 parts of 4-methylbonzene~ulfonic acid, 80 part~ of
butanol and 180 parts of benzeno i~ stirred and reflwced for
24 hours with water-scparator. The r~action mixture i8 evapora-
ted and the residu~ i~ diflsolvcd in trichlorom~thane. The
~olution i~ stirred with ~ilica gel for 30 minute~, The latter
i~ filtered of and the filtrate i~ evaporated, yielding A~B-
2-(bromomethyl3-2-(2, 4-dichlorophenyl)-4-(2, 5 dimethylphen-
l~xymethyl)-l, 3'-dioxolanc as a residue. -`
.,. . , ":
Example XXVII ' ~ '
`
Following the procedure of Example XXVI and u~ing
equivalent amounts of thc appropriate starting material~ and
the indicated so'lvent, the following dioxolanes are obtained
a~ a residue:
`' . `
BrCH2 ~R6 ` ~ .`
Ci~O '
C;~2 ' '
,.:
Isomer R6 ~ R5 Solvent '
A+B 2~ 4-(Cl)~ 2-Cl-~6H4 benzene
A+B 2, 4-(Cl)2 2, 6-~Cl)Z-cbH3 benzene
A+B Z, 4 (C )2 6 4 benzene
A~B 2-Br 4-Br-C6H4 benzene
--55--
.
~65i~73
l~omer R~ ~5 Solvent
A+B 2, 4-(Cl)2 2-Cl, 6-CH3-G6~3` methylbenzene
A+B 2, 4-~C 1)2 2~ 3-(Cl)2~c6H3 meShylbenzene
A~B 2, 4-~l)2 2, 4, 6-(Cl)3-C6H2 ben2:ene
A-~B 2, 4-~Cl)2 2-CI, 4-,~C ~C~13)3~- ben~ne
: ~ C6H3
A~B ~ -(Cl)2 2, 4, 5-(Cl)3~C~6~2 ben~ene
A~B ~ )2 2, 5-(Br)2~ 4-CH3-C6E~12 benzene
A~B 2, 4_(Cl)2 2 C2H5 C6 ~15 benzene .
A~B 2-Cl 4-Br-C6H4 benzene
A+B 2, 4_~Cl~2 2, 6-(cH3)2-c6H3 methylbenzene
A 2, 4-(Cl)2 6-Br-2-naphthalenyl benzene
2, 4-(C1)2 2-(C6~s)-C6H4 dimethylhenzene
.~
. : '
Example XXVIII
; .
Following the procedure of Example XX~I and ~sing
equivalent amounts of the appropriate ~tarting rhaterial~ and
methylbenzene as a ~olvent,the following dioxolanes are --:-
obtained after puriication of the produc~ by column-chromato-
graphy over ~llica gel u~ing trichloromethane a~ eluent:
2-(bromomethyl) -4-(2 -chloro- S -methylphenoxymethyl)-2 - ` . (2, 4-dichlorophenyl~-l, 3-dioxolane as an oily residue;
,~ , . - , .:
A~B-2-(bromomethyl)-2-~2, 4-dichlorophenyl)-4-(3, 4, 5-
tris:hlorophenoxymethyl)- l j 3 -dioxolane as a r e ~ idue,
: . ` ' - '
--56--
.
. . .
~ 58'73
Example XXIX
A mixture of 222.5 parts of 2-bromo-1-(2,4-dichloro-
phenyl)-l-ethanone, 250 parts of 3-(4-bromophenoxy)-1,2-propanediol,
50 parts of 4-methylbenzenesulfonic acid and 3150 parts of benzene
is stirred and refluxed in a four-necked, round-bottom flask,
equipped with a water-trap. After 16 hours the theoret:Lcal amount
oE water is evolved. The reaction mixture is allowed to cool to room
temperature and washed successively with diluted sodium hydroxide
solution and twice with water. The solvent is dried and removed in
vacuo. The residue is triturated in methanol. The product is filtered
off (the filtrate is set aside) and crystallized from butanol,
yielding A-2-(bromomethyl~-4-(p-bromophenoxymethyl)-2-(2,4-
dichlorophenyl)-1,3-dioxolane.
The filtrate (see above) is evaporated. The residue is
dissolved in 210 parts of 2,2'-oxybispropane and the solution is
allowed to crystallize. The precipitated product is filtered off and
discarded. The filtrate is evaporated and the residue is dissolved -
in 400 parts of a mixture of hexane and trichloromethane (3 : 1 by ;-
volume). The undissolved part is filtered off and discarded. The
filtrate is purified twice by column-chromatography over silica gel
using a mixture of hexane and trichloromethane (3 : 1 by volume) as
eluent. The pure fractions are collected and the eluent is evaporated.
The residue solidifies on triturating in petroluemether. The product
is filtered off and dried9 yielding B-2-(bromomethyl)-4-(4-bromo-
phenoxymethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane.
Example XXX
A mixture of 15.2 parts of 2-bromo-1-(2,4-dichlorophenyl)-
ethanone, 16.7 parts of 3-(3-chloro-[1,1'-biphenyl]-4-yloxy)-1,2-
propanediol, 3 parts of 4-methylbenzenesulfonic acid, 40 parts of
butanol and 255 parts of dimethylbenzene is stirred and refluxed for
~;58~3 ~ ::
2 days with water~separator. The reaction mixture is allowed to cool
to room temperature and 2,2'-oxybispropane i5 added. The organic
phase is washed with a diluted sodium hydroxide solution SN and with
water, dried, filtered and evaporated. The residue is triturated in a
mixture of 2,2'-oxybispropane and petroleumether. The product is
- filtered off (the filtrate is set aside) and dried, yielding 12.5 parts
of A-2-(bromomethyl)-4- (3-chloro-[1,1'-biphenyl]-4-yloxymethyl)-
2-(2,4-dichlorophenyl~-1,3-dioxolane.
The filtrate (see above) is evaporated. The residue is dis-
solved in trichloromethane and the solution is stirred with silica gel.
The latter is filtered off and the fitrate is evaporated, yielding 10 ~; -
parts of A+B-2-(bromomethyl)-4-(3-chloro-[1,1'-biphenyl]-4-yloxymethyl)-
2-(2,4-dichlorophenyl)-1,3-dioxolane as a residue.
Example XXXI ~
A mixture of 18.1 parts of 3-[4-(phenylmethyl)phenoxy]- `
1,2-propanediol, 13.4 parts of 2-bromo~ 2,4-dichlorophenyl)ethanone,
3 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and
225 parts of methylbenzene is stirred and refluxed over week-end. The
` reaction mixture is evaporated and the oily residue is triturated in
methanol. The product is filtered off (the filtrate is set aside), yielding
15 parts of A-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-[4-~phenyl-
methyl)phenoxymethyl]-1,3-dioxolane; mp. 96C.
The filtrate, which was set aside, is evaporated. The oily ~ `
residue is purified by column-chromatography over silica gel using a mix-
ture of trichloromethane and 20% of hexane as eluent. The pure fractions
are collected and the eluent is evaporated, yielding 13 parts of B-2-
(bromomethyl)-2-(2,4-dichlorophenyl)-4-[4-(phenylmethyl)phenoxy-
methyl]-1,3-dioxolane as an oily residue.
-58-
:~,
Exa~ple XXXII -
~." . '~
A mixture of 14~9 parts of 3-(2-nitrophenoxy)-1,2-propanediol,
13.4 parts of 2-bromo-1-(2,4-dichlorophenyl)ethanone, 3 parts of
4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts of
methylbenzene is stirred and refluxed over week-end. The reaction
mixture is evaporated and the oily residue is dissolved in trichloro-
methane. The solution is washed with a diluted sodlum hydroxide
solution 20% and with water, dried, filtçred and evaporated. The oily
residue is crystallized from 2,2'-oxybispropane while stirring. The
product is filtered off (the filtrate is set aside), yielding 8.5 parts
of A-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(2-nitrophenoxymethyl)-
1,3-dioxolane. -;~
The filtrate which was set aside, is evaporated. The
oily residue is purified twice by column-chromatography over silica
gel using, first trichloromethane and second a mixture of trichloromethane
and 20% of hexane as eluent. The pure fractions are collected and the
eluent is evaporated, yièlding 14.5 parts of B-2-(bromomethyl)-2-(2,4- ~-
dichlorophenyl)-4-(2-nitrophenoxymethyl)-1,3-dioxolane as an oily
residue.
Example XXXIII -
A mixture of 13.6 parts of 2-bromo-1-(2,4-dichlorophenyl)-
l-ethanone, 15.8 parts of 3-(4-bromophenylthio)-1,2-propanediol,
3 parts of 4-methylbenzenesulfonic acid, 180 parts of butanol
and 90 parts of benzene is stirred and refluxed for 12 hours with
water-separator. The reaction mixture is evaporated and the
residue is dissolved in trichloromethane. The solution is stirred
with silica gel for 30 minutes. The latter is filtered off and
the filtrate is evaporated, yielding A t B 2-(bromomethyl)-4-
(4-bromophenylthiomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane
as a residue.
-59-
,St373
Example XXXTV
Foll~wing the procedure of Example XXXIII and using . -:
equivalent amounts of the appropriate ~tarting material~, the
follo-ving dioz~olanes are prepared:
A ~ 2 -(bromomethyl)-Z - (2, 4 -dichlo rophenyl)_~ -(phenylehio -
m~thyl)-1,3-dioxolane as a rc~idue
A+B-2-(bromom~thyl)-2-(2, 4-dichlorophenyl)-4_~4_nuoro_ . ~ :
phenyl)thiomethyl7-1, 3-dioxolane a~ a re~idue
.
Example XXXV . : .
:. :
A mixture of 19.8 part~ of 3-~4-bromo~?hcnoxy)-1,2-propanediol,
15,6 parts of 2-(bromomethyl)-2-~3,5-dichlorophenyl-1,3-dioxolane,
: . 4 pares o 4-~nethylbenzene6ulfonic acid, ~0 pa~ts of butanol and Z25
: . .
; . parts of benzene is stirred and refluxed for ~ days with ~vater-8eparator.
The reaction mixture i8 allowed to cool to room temperature and the
- - eol~rent i8 removed by evaporation in vacuo, The residue i8 triturated
~n methanol. The product is filtered o~f and crystallized from 2-propanol ~ .
y~elding 5,5 parts (~2%) of ~-2-(bromomethyl)-4-(4-bromophenoxymeShyl~
2-(3, 5-dichlorophenyl)-1, 3-dioxolane.
:
. '
.
. - . ...
- - 6 0- - -
. . :;:
~365~3P73
Exam~le XXXVI
Following the procedure of Example XXXV and using equi-
valent amounts of the appropriate starting materials, the following
dioxolanes are prepared by carrying out the reaction in the indicated
solvent:
Using methylbenzene as a solvent there are prepared:
A-2-(bromomethyl)-4-(4-bromophenoxymethyl)-2-(4-chloro-2-methyl-
phenyl)-1,3~dioxolane; mp. :L55C;
A-2-(bromomethyl)-4-(4-bromophenoxymethyl)-2-(3-bromophenyl)-1,3-dioxolane;
mp. 92.2C;
A-2-(bromomethyl)-2-(4-bromo-2-methylphenyl)-4-(4-bromophenoxymethyl)-1,3-
dioxolane;
A-2-(bromomethyl)-2-(3-bromo-4-methylphenyl)-4-(4-bromophenoxymethyl)-1,3-
dioxolane; mp. 100C;
A-4-[2-(bromomethyl)-4-(4-bromophenoxymethyl)-1,3-dioxolane-2yl]-benzonitrile;
A-2-(bromomethyl)-4-(4-bromophenoxymethyl)-2-(3-nitrophenyl)-1,3-dioxolane;
and
A-2-(bromomethyl)-4-(4-bromophenoxymethyl)-2-(2,3-dichlorophenyl)-173-
dioxolane.
Using dimethylbenzene as a solvent there are prepared:
A+~-4-([1,1'-biphenyl]-4-yloxymethyl)-2-(bromomethyl)-2-(2-naphthalenyl)-1,3-
dioxolane; mp. 160.8C;
A-4-([1,1'-biphenyl]-4-yloxymethyl)-2-(bromomethyl)-2-(2-chloro-4-methoxy-
phenyl)-1,3-dioxolane;
-61-
37~ ~
~B-2-(bromomethyl)-4-ethyl-2-(2,3,4-trichlorophenyl)-1,3-dioxolane; bp.
145C at 0.1 mm.pressure;
A+B-4-([1,1~-biphenyl]-4-yloxymethyl)-2-(bromomethyl)-2-(2,4,5-trichloro-
phenyl)-1,3-dioxolane as a residue;
A+B-2-(bromomethyl)-2-(2,3-dichloropheny:L)-4-ethyl-L,3-dioxolane; bp. 131-
133C at 0.1 mm. pressure;
A+B-2-(bromomethyl)-2-(2-chloro-4-methoxyphenyl)-4-ethyl-1,3-dioxolane; bp.
:,:
142-144C at 0.3 mm. pressure;
A-~B-2-(bromomethyl)-2-(4-chloro-2-methylphenyl)-4-ethyl-1,3-dioxolane;
bp. 118C at 0.15 mm. pressure;
A+B-2-(bromomethyl)-4-ethyl-2-(2-naphthalenyl)-1,3-dioxolane as a residue; and
2-(bromomethyl)-2-(2,4-dichlorophenyl)-4- [2-(4-methylphenyl)ethyl]-1,3-
dioxolane as a residue.
Example XX~
A mixture of 13.6 parts oE 2-bromo-1-(2,4-dichlorophenyl)=
l-ethanone, 14.1 parts of 1- [2-(2,4-dichlorophenyl)ethyl]ethanediol,
3 parts of 4-methylbenzenesulfonic acid, 80 parts of butanol and 180
parts of benzene is stirred and refluxed for 24 hours. The reaction ~ -
mixture is evaporated and the residue is stirred for 2 hours with ;
160 parts of methanol. The precipitated product is filtered off,
yielding 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-[2-~2,4-dichloro-
phenyl)ethyl]-1,3-dioxolane. ~
. :,.
--62--
,' ' :'' '' ' . - ; ,', ~ ' ~ . . ,' ` - ', . :.
~658~3
Example XXXVIII
Following the procedure of Example XXXVII and using
equivalent amounts of the appropriate starting materials, the
following dioxolanes are prepared by carrying out the reaction
in the indicated solvent.
Using benzene as a solvent there are prepared:
2-(bromomethyl)-4-[2-(2-chlorophenyl)ethyl]-2-(2,4-dichlorophenyl)-1,3-
dioxolane;
2-(bromomethyl)-2-(2,~-dichlorophenyl)-4-[2-(2,6-dichlorophenyl)e~hyl]-1,3-
dioxolane; and
A+B-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-[2-(4-methoxyphenyl)ethyl]-1,
3-dioxolane.
In methylbenzene as a solvent are prepared:
2-(bromomethyl)-4-~2-(4-chlorophenyl)ethyl]-2-(2,4-dichlorophenyl)-1,3-
dioxolane as a residue; and
2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(2-phenylethyl)-1,3-dioxolane as
a residue.
In dimethylbenzene as a solvent are prepared: ~-
A+B-2-(bromomethyl)-2-~2,4-dichlorophenyl)-4-(phenylmethyl)-1,3-dioxolane
as a residue;
A+B-2-(bromomethyl)-4-(4-chlorophenylmethyl)-2-(2,4-dichlorophenyl)-1,3-
dioxolane; and
A+B-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(4-methoxyphenyl methyl)-1,3-
dioxolane as a residue.
-63-
~.~6~3'73 :
Example X~XIX
A mixture of 13.5 parts of 1~2-butanediol, 37.5 parts
2-bromo~l-(2,4-dichlorophenyl)ethanone, 2 parts of 4-methyl-
benzenesulfonic acid, 40 parts of butanol and 225 parts of methyl-
benzene is stirred and refluxed for 24 hours with water-Separator.
The reaCtion miXture iS cooled, washed twice With a sodium
bicarbonate solution, dried, filtered and evaporated. The residue
is distilled, yielding 38 parts (80%) of A-~B-2-(bromomethyl)-2-
(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolane; bp. 125-130C at 0.1
10mm. pressure.
Example XL
Following the procedure of Example XXXIX and using
equivalent amounts of the appropriate starting materials, the
following dioxolanes are prepared:
Br-CH ~ A + B
R I - I -
~ . . . ._. _ __ _ . .. . .. . .... ~
R R boiling point ~ ~
... .:
C2H5 2-Cl 97-99C at 0.05 mm. pressure
C2H5 2-CH3 86-88C at 0.05 mm. pressure
C2H5 4-CH3 100C at 0.05 mm. pressure
_ C2~5 2-Br 114-115C at 0.05 mm. pressure
____________ ___________________ ____------------ .~
-64-
373
.
R R boiling point
-
2 5 3-C1 140C at 0.6 mm. pressure -
C2H5 2-Cl,4-Br
2 5 4-OCH3 122C at 0.15 mm. pressure
C2H5 3,4,5-(Cl) 135C at 0.05 mm. pressure
nc3H7 2~4-(C1)2 102-125C at 0.05 mm. pressure
4 9 2~4~(Cl)2 137-139C at 0.05 mm. pressure
nC5H11 2,4-(C1)2 140-145C at 0.03 mm. pressure
6 13 2,4-(C1)2 163-170C at 0.1 mm. pressure
10nC7H15 2,4-(C1)2 1~0-165C at 0.05 mm. pressure
nC8H17 2,4-(C1)2 180-190C at 0.05 mm. pressure
C}l20H 2,4-(C1)2 145-150C at 0.05 mm. pressure
_ .:
Example XLI
To a stirred and warm solution of 6.5 parts of 1,2-butanediol,
13 parts of 1-(4-chloro-2-methoxyphenyl)ethanone and 40 parts of
butanol are added dropwise (slowly) 5.7 parts of bromine at about 40C.
After stirring for 30 minutes9 there are added 2 parts of 4-methyl-
benzenesulfonic acid and 225 parts of methylbenzene and the whole
is stirred and refluxed overnight with water-separator. The reaction
mixture is cooled, washed with a potassium carbonate solution9 dried
filtered and evaporated. The residue is distilled, yielding 17 parts
(63%) of A+B-2-(bromomethyl)-2-(4-chloro-2-methoxyphenyl)-4-
ethyl-1~3-dioxolane; bp. 135-140C at 0.3 mm. pressure. ;
-65-
~:, ,. . ' '' .
`
13xample XLII
Following the procedure of Example XLI and using an equi-
valent amount of l- C2,4,5-trichlorophenyl)ethanone in place of the
1-(4-chloro-2-methoxyphenyl~ethanone, there is obtained:
A+B-2-(bromomethyl)-4-ethyl-2-(2,4,5-trichlorophenyl)-1,3-dioxolane; bp.
145 C at 0.2 mm. pressure.
Example XIIII
To a stirred solution of 53 parts of 1-(2,4-dibromophenyl)-
ethanone in 105 parts of l,l'-o~ybisethane, are added dropwise,
during a 2 hours-period, 32 parts of bromine. Then there are added
carefully 68 parts of l~l-imidazole and 135 parts of N,N-dimethyl-
formamide and the whole is stirred for 2 hours at 50C. Upo~l
the addition of water, the product precipitates. It is filtered off,
washed with water and dissolved in trichloromethane. The solution
is dried, filtered and evaporated. The residue is converted into the ;
hydrochloride salt in 2-propanone and 2-propanol. Upon the addition : -
of 2,2'-oxybispropane, the product is crystallized. It is filtered off,
washed with 2-propanone and recrystallized from a mixture of ethanol - -
and 2,2'-oxybispropane, yielding 28.3 parts oE 1-(2,4-dibromophenyl)-
2-(lH-imidazol-l-yl)ethanone hydrochloride; mp. 204.7C.
Example XLIV
To a stirred solution of 78.7 parts of 2-bromo-1-(2-chloro-4-
fluorophenyl)ethanone in 140 parts of l,l'-oxybisethane are added
carefully 106.4 parts of lH-imidazole. Upon completion, there are
added 180 parts of N,N-dimethylfonnamide and the whole is stirred
for 2 hours at 50C. After the addition of water, the product is extracted
twice with trichloromethane. The combined extracts are washed three
times with water, dried, filtered and evaporated. The residue is conver-
ted into the hydrochloride salt in 4-methyl-2-pentanone, 2,2'-oxybis-
propane and 2-propanol. The salt is filtered off and crystallized from a
--66--
- .- ' '
~;515~3
mixture of ethanol and 2,2'-oxybispropane, yielding 1.5 parts of
1-(2-chloro-4-fluarophenyl)-2-tlH-imidaæol-l-yl)ethanone hydrochloride;
mp. 197.4C.
Example XLV
A. To a stirred mixture of 67.2 parts of A+B-2-(bromomethyl)-
2-(2,4-dichlorophenyl)-1,3-dioxolane-4-methanol and lO0 parts oE
pyridine are added dropwise 27.2 parts of benzoyl chloride while
cooling at a temperature below 10C. Upon completion, stirrlng is
continued for 2.50 hours at room temperature. The reaction ~ixture
is poured onto water and the product is extracted with trichloromethane.
The extract is washed successively with a diluted hydrochloric acid
solution, to remove the last traces of pyridine9 and with water, dried
filtered and evaporated. The oily residue is triturated in methanol.
The solid product is filtered off (the filtrate is set aside) and crystal-
lized twice from ethanol, yielding 28 parts of cis 2-(bromomethyl)-2-
(2,4-dichlorophenyl)-1,3-dioxolan-4-ylmethyl benzoate; mp. 118.3C.
The filtrate (see above) is evaporated. The oily residue is purified
by column-chromatography over silica gel using 2,2'-oxybispropane
as eluent. The pure fractions are collected and the eluent is evaporated.
The oily residue is triturated in methanol. The solid product is ~ ~
purified by column-chromatography over silica gel using trichloro- ~ ;
methane and hexane (30:70) as eluent. The pure fractions are collected
and the eluent is evaporated, yielding 17.5 parts of trans-2-(bromo-
methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-ylmethyl benzoate,
mp. 68.6C. ~
B. A mixture of 12 parts of cis-2-(bromomethyl)-2- ~ -
(2,4-dichlorophenyl~-1,3-dioxolan-4-ylmethyl benzoate, 7.5 parts
of sodium hydroxide solution 60%, 100 parts of water and 200 parts
of 1,4-dioxane is stirred and refluxed for 1 hour. The reaction mixture
-67-
.. . ~ - . . : , - -. .
65~73
is cooled, poured onto water and the product is extracted with tri- ;
chloromethane. The extract is washed with water, dried, filtered
and evaporated. The oily residue is purified by column-chromatography
over silica gel using a mixture of trichloromethane, hexane and
methanol (50:49:1) as eluent. The pure fractions are collected and
the eluent is evaporated, yielding 4.5 parts of cls-2-(bromomethyl)-
2-(2,4-dichlorophenyl)-1,3-dioxolane-4-methanol as a residue.
Following the procedure of Example XLV-B and using
an equivalent amount of trans-2-(bromomethyl)-2- (2, 4-dichloro-
phenyl)-1,3-dioxolan-4-ylmethyl benzoate in place of the cis-2-
(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-ylmethyl
benzoate, there is obtained:
trans-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane-4-methanol
as a residue~ ~
Example XLVI ~ ;
A mixture of 4.5 parts of methanesulfonyl chloride, 10 parts
of CiS-2- (2, 4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)-1,3-dioxolane-4- ~-methanol and 50 parts of pyridine is allowed to stand for 3 hours at ~ -
room temperature. The reaction mixture is poured onto water. The
precipitated product is filtered off and crystallized from benzene,
yielding 10.3 parts (87%) of cis-2-(2,4-dichlorophenyl) 2-(1~-
imidazol-l-ylmethyl)-1,3-dioxolan-4-ylmethyl methanesulfonate; mp.
111.7C.
-68-
iS~73
Example XLVII
A mixture of 32 parts of 1,2,4~butanetriol, 60 parts of 2-bromo-
1-(2,4-dichlorophenyl)ethanone, 2 parts of 4-methylbenzenesulfonic acid,
40 parts of butanol and 225 parts of methylbenzene is stirred and refluxed
overnight with water-separator. The reaction mixture is cooled, washed
with a potassium carbonate solution, dried, Eil~ered and evaporated. The
residue is purified by column-chromatography over silica gel uslng a
mixture of trichloromethane and methanol (99:1) as eluent. The pure
fractions are collected and the eluent is evaporated, y:Leld-ing 34 parts
(43%) of ~+B-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane-4-ethanol
as a residue.
.7~
To a stirred mixture of 20 parts of A~B-2-(bromomethyl)-2-(2,4-
dichlorophenyl)-1,3-dioxolane-4-ethanol and S0 parts of pyridine are
added dropwise 6.9 parts of methanesulfonyl chloride. Upon completion,
stirring at room temperature is continued for 2 hours. The reaction mixture
is poured onto water and the product is extracted twice with l,l'oxybis- -
ethane. The combined extracts are washed successively twice with a diluted
hydrochloric acid solution and once with water, dried, filtered and
evaporated, yielding 25 parts (100%) of A+B-{2-[2-(bromomethyl)-2-(2,4- ;;
dichlorophenyl)-1,3-dioxolan-4-yl]ethyl3methanesulfonate as a residue.
To a stirred mlxture of 25 parts of A+B-{2-[2-(bromomethyl)- -;~
2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]ethyl}methanesulfonate and 100
parts of dimethylsulfoxide are added 2.2 parts of sodium hydride dis-
persion 78% at room temperature. Stirring is continued for 3 hours at
50C. The reaction mixture is poured onto water and the product is extract-
ed twice with 2,2'-oxybispropane. The combined extracts are washed twice ~-
with water, dried, filtered and evaporated. The residue is purified by
column-chromatography over silica gel using trichloromethane as eluent.
The pure fractions are collected and the eluent is evaporated, yiélding
15 parts (79%) of A+B-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-ethenyl-13
3-dioxolane as a residue. -
-69- ~
': '.
~658~3
Example LVIII
A mixture of 1.1 parts of imidazole, 1 part of 2-(bromo-
methyl)-2,4-bis(4~chlorophenyl~-1,3-dioxolane, 0.4 parts of
potassium iodide and 20 parts of dimethylformamide is stirred and
refluxed for 12 hours. Water is added and the product is extracted
with l,l'-oxybisethane. The extract is washed twice with water, dried,
filtered and evaporated. The residue oE 1-[2~4-bis(4-chlorophenyl)-
1,3-dioxolan-2-ylmethyl]imidazole is converted into the nitrate salt.
The crude salt is filtered oEf and crystallized from a mixture of
2-propanol and 2,2~-oxybispropane, yielding 1-[2,4-bis(4-chlorophenyl)-
1,3-dioxolan-2-ylmethyl]imidazole nitrate; mp. 192.3C.
Example IL
A mixture of 7 parts of imidazole, 7.5 parts of 2-(bromomethyl)-
2-(4-chlorophenyl)-4-phenyl-1,3-dioxolane, 2 parts of sodium iodide
and 100 parts of N,N-dimethylformamide is stirred and refluxed for 48
hours. The reaction mixture is allowed to cool to room temperature and
is poured into water. The product is extracted twice with benzene. The
extract is washed twice with water and the solvent is removed in vacuo.
The residue of 1-[2-(4-chlorophenyl)-4-phenyl-1,3-dioxolan-2-ylmethyl]-
imidazole is converted into the nitrate salt in 4-methyl 2-pentanone and
2,2'-oxybispropane. The crude salt is filtered off and crystallized from
4-methyl-2-pentanone 3 yielding 1-[2-(4-chlorophenyl)-4-phenyl-1,3-
dioxolan-2-ylmethyl]imidazole nitrate; mp. 153.2G.
'`': '' ' ,
-70-
;
--
~)6S~3
Exampl~ L
- Following the procedul~ of Examplc IL and u~ing
equiv~l~nt amounts of the appropriate starting material6 -
th~ followin~ imidazole acid addition aalts are prepared: :
N ~ ,
., ~J
Melting Point : v-
R ~7 Acid Salt of Salt
. . .
4 -Cl 2, 4~ z HN03 196 . 6 C
4 Br 4-CI HN03 152. 6DC
4-Br 2, 4_(Gl)2 H~03 205. 3C
2~ 4-(Cl)2 ~ . 2(COOH)z 107. 7C
4-OCH3 4-Cl HN03 196. 3C
2~ 4-(Cl)2 HN03 163. 8C
2,4-(C1)2 4-Cl 1 1/2(COOH)2 119.9C
4-(::1 HN03 134. 7~C
4-C1 2-Cl HN03 . 183, 8C
2-(:~1 2~4-(Cl)z HN03 164.2~C
2,4-(C1~2 2-CI HN03 151C;
4-Br Z-Cl HN03 194. 7G
2,4-(Cl)z 2,4-(C1)2 HN03 161 2C
4-Br - HN03 156. 5C
- 4-Br HN03 131 . 1 C
4-CH3 2~4-(Cl)z ~N03 193.6C
4-Br 4-Br HNV3 144. 3(::
4-CH3 4-Cl HN03 zao. 8 C
4-Cl . 4-Br HN03 145. 2C
-71-
~ 6~373
.
.
.6 R7 Acid Salt Melting Poin~
of Salt
J.-C~13 4-Br HN03 210. 5C
3-C1 2, 4-(Cl)zHN03 165. 4C
2-C1 4-Br HN03 184. 1 C
4-CH3 2-Cl HN03 207. 5C~
4-C1 4-C}-i3 HN03 144. 3C
4-Br 4-C~13 HN03 140. 2C
~-Cl 4-F HN03 163. 2C
4-Br 4-F HN03 179, 3C
' :`,:
` " . '~ :''
Example LI
-
~' .
`~ A mixture of 13,b part6 of imidazolc, 18.5 part~ of 2-
~i~omomethyl)-2~ chlorophenyl)-4-(p-chlorophcnyl)-1, 3-dioxolane,
4 part~ of sodium iodide and 150 parts of dimethylformamide is
~tirred and refluxed ~or 72 hour6, Water i~ added and the product is
extr~cted twice with diisopropylether. The combined extracts axe wa~hed
twicc with watcr, dried, iltered and eYaporated. The residue i~ purified
by column-chromatography over ~ilica gel uaing trichloromethane as
eluent. The pure fractions are collected and the eluent i~ evaporated.
The re~idue of 1-~2-(o-chlorophenyl) 4~ chlorophenyl)-1, 3-dioxolan-
2-ylmethy~7imidazol~ i~ con~rerted into the nitrate ~alt in 2-propanol
and diiaopropylether. The aalt i~ filtered off and ery6tallized from a ~ ~ -
mixtur~ of ethanol and dii60propylether, yielding l-~Z-(o-chlorophenyl)- -
; 4-(~-chlorophenyl)-1,3-dioxolan-2-ylmethyl~imidazole nltrate; mp. 183.1-C
. . ' '' ' ~''
- ~ .
,.,
--72--
. .
3L06S8~73
Example LII ~ -
'.' , "' . .
- Following the procedure of l~xample LI and u~ing
an cquivalent amount of 2-(bromomethyl)~4-~4_bromophenyl~_
2-(2, 4-dichlorophenyl)-1, 3-dioxolane in place of the 2-(bromo_
methyl)-2-(2-chlorophonyl)-4-(4--chlorophcnyl)-1, 3-dioxolane m
used therein, there iB prepared: .
1-~-(4-bromophenyI)-2-(2, 4-dichloropheny1)_1, 3-dioxolane-
2-ylmcthy~;7imidazole nitrate; ~p. 141. 9C.
..
,~
~xample LIII
To a stirred ~olution of 2, 3 parts of ~odium in
80 part~ of methanol are added 6. 8 parts of imidazole,
follo~ed by the addition of 100 parts of dimethylformamide
and the methanol i5 removed at atmospheric pres~ure till an - -
internal temperature of 13QC i8 reached. Then th~re are
added 7 parts of A-2-(bromomethyl)-2-(p-chlorop~enyI)-4_
(4-chloro-o-tolyloxymethyl)-1, 3 dioxolane and the mixture ia
etirred and refluxed for 3 hours. Thc reaction mixture iY ::
poured onto wates and the product i8 extracted with benzene,
The extract i8 dried and evaporated in vacuo. The residue
of A~l -~-tp-chlorophenyl)-4-(4-chloro- o-tolyloxymethyl)-
1, 3-dioxolan-2-ylmethy~7imidaxole i6 converted into the
nitrate salt in 2-propanol. Upon thc addition of dii~oprop~l-
ether, tke salt i~ precipltated. It i8 filtered off a~d crystallized
from a mixture of methanol and diisopropylether, yielding cis
- I-~-(~-chlo~ophenyl)-4-(4-chloro-o-tolyloxymethyl)-l, 3-
dioxolan-2-ylmethy~7imida~ole nitratc; n~p. 164. 3C.
.:
. ' , :': .
-73-
:' '
.
~6513~73 ::
Example LIV
Following the procedure of Example LIII and using equivalent
amounts ofthe appropriate starting materials, the following imidazoles
and imidazole acid addition salts are prepared:
,
; lO R '
Acid Salt
Isomer 6 7Base Melting Point of Salt
trans 4-C1 4-Cl92-CH3 HNO3 190 - 190.7 --
cis 4-C1 4-CH3 HNO3 140.2
trans 4-C1 4-CH3 HNO3 160
trans 4-C1 4-Cl HNO3 171.8 - 176.9
cis 4-C1 4-Cl HNO3 165.3 - 169.6
B 4-C1 2,4-Cl HNO3 160 - 165.3
cis 4-C1 4-F HNO3 172.3 - 174.5
trans 4-C1 4-F HNO3 175.9 ~;
A 4-C1 2-CH3 HN03 134.6 - 145.4
B 4-C1 2-CH3 HN03 156.6 - 161.6
B 4-C1 2-Cl HNO3 170.5
B 4-C1 4-OCH3 ~NO3 133.2
-74-
~LV6~ii873 :
Acid Salt
Isomer R R base Melting Point of Salt ;
A 4-C1 2,4-(Cl)2 base 175.4 - 179.5C
A 4-C1 2-Cl base 140.8 - 143.6C
A 4-C1 4-OCH3 base 111.1C
Example LV
To a s~irred solution of 4.6 parts o~ sodium in 160 parts
of methanol are added successively 13.6 parts of imidazole, 300 parts
of dimethylformamide and 4 parts oE sodium iodide. The metbanol is
distilled off at atmospheric pressure till an internal temperature
of 130C is reached. Then there are added 25.9 parts of A ~ B-2- -~
(bromomethyl)-2-(p-chlorophenyl~-4-(2,6-dichlorophenoxymethyl)-1,3-
dioxolane and the whole is stirred at reflux temperature for 2 hours.
The reaction mixture is allowed to cool to room temperature and
poured onto water. The product is extracted twice with benzene.
The combined extracts are washed twice with water, dried, and
evaporated in vacuo. The residue, containing the "A" and "B"- -
isomers, is chromatographed over silica gel with chloroform as
eluent. The "A"=isomer is collected as an oily free base and is
converted into the nitrate salt in 2-propanol. The crude salt is
crystallized from 2-propanol, yielding 3,8 parts of A-1-[2-(~-
chlorophenyl)-4-(2,6-dichlorophenoxymethyl)-1,3-dioxolan-2-ylmethyl]-
imidazole nitrate; mp. 145.8C. The "B"-isomer is also collected as
an oily free base and is converted into the nitrate salt in 2-propanol
and diisopropylether. The crude salt is crystallized from 2-propanol,
yielding 2.2 parts of ~-1-[2-(p-chlorophenyl~-4-(2~6-dichlorophen
m thyl)-l,3-diox~lan-2-ylmethyl]imidazole nitrate mp. 197-200.5C.
-75-
,'~.,': '
~xample LVI
Following the procedure of Example LV and using equivalent
amounts of the appropriate starting materials, the following imidazoles
and imidazole acid addition salts are prepared:
A-1-[2-(2,4-dichlorophenyl)-4-~o-tolyloxymethy~-1,3-dioxol~n-2 ylmethyl]~
imidazole nitrate; mp. 156.2C;
B-1-[2-(2,4-dichlorophenyl)-4-(o-tolyloxymethyl)-1,3-dioxolan-2-ylmethyl]-
imidazole sesquioxalate; mp. 138.5C;
A-1-[2-(2,4-dichlorophenyl)-4-(2,6-dimethylphenoxymethyl)-1,3-dioxolan-2-
ylmethyl]-lH-imidazole nitrate; mp. 155.6C;and CI
A+~-1-[2-(2,4-dichlorophenyl)-4-(2,6-dimethylphenoxymethyl)-1,3-dioxolan-
2-ylmethyl]-lH-imidazole nitrate; mp. 134.5C
Example LVII
A mixture of 6.8 parts of imidazole, 7.8 parts of A-2-(bromo-
methyl)-2-(2,4-dichlorophenyl)-4-(phenoxymethyl)-1,3-dioxolane, 4 parts
of sodium iodide and 150 parts of dimethylformamide is stirred and re-
fluxed for 3 days. The reaction mixture is allowed to cool to room
temperature, poured into water and the product is extracted twice with
diisopropylether. The combined extracts containing A-1-[2-(2,4-dichloro-
phenyl)-4-(phenoxymethyl)-1,3-dioxolan-2-ylmethyl}imidazole are washed
twice with water and acidified with an excess of a concentrated nitric
acid solution. The salt is filtered off and crystallized from a mixture
of ethanol and diisopropylether, yielding 5.6 parts of A-l-E2-(2,4-di-
chlorophenyl)-4-(phenoxymethyl)-1,3-dioxolan-2-ylmethyl]imidazole nitrate~
mp. 180.5C.
-76-
Example LVIII
Following the procedure of Example LVII and using equivalent
amounts of the appropriate starting materials, the ~ollowing imidazoles
and imidazole acid addition salts are prepared:
N
\o~ <o ~R6
R -0-CH2- l J
"
Acid Salt
6 5 Melting or
Isomer R R Point Base
A 2,4-(C1)2 3,4-(C1)2-C6H3 152.1C HN0
A 2,4-(C1)2 3-Cl-C H 120.9C HN0
A + B 2,4-(C1)2 2-CH ,4-Cl-C H 121.9-~ HN0
A 2,4-(C1)2 2~4-(Br)2-c6H3 164.9C HN03
cis 2,4-(C1)2 2-F-C6H4 135.9C H -~
A _ 4-Br-C H 167.6C HN03
B 2,4-(C1)2 4-Br-C6H 131.1C HN0
cis 2,4-(C1)2 4-F-C H 151-152C HN0 ~ -
A 2,4-(C1)2 4-CH -C H 141.8C HN03
B 2,4-(C1)2 4-CH -C H 145.1C (COOH)2
cis 2,4-(C1)2 3 C6 4 184.7C ( )2
cis 2,4-(C1)2 4-Cl-C H 152.7C 3 ;
A 2,4-(C1)2 2,4-(Cl)2-C6H3 146.5C HN03
A 2,4-(C1)2 4-Br-C H 158.9C HN0
A 2,4-(C1)2 3,5-(CH3)2~4-Cl-c6H2 185.7C HN03 ~ -
A 2,4-(C1)2 4-CN-C H 208C HN03 -
A 2,4-(C1)2 3 6 4 110.6C 2(COOH)2
A 2,4-(C1)2 6-Br-2-naphthalenyl 195.5C 3
cis 2,4-(C1)2 2-naphthalenyl 156.3C HN0
A + B 2,4-(C1)2 4-Cl-2-naphthalenyl 136.7C 3
cis 2,4-(C1)2 4-Br-C H 121.8C base
-77-
: .,
., , ' - ~ ' ' .
~: . .. ~ ,
~0;~373
- :~
Example LIX
.. _-- , '. ,
A mixture oî 13.6 parts of imldazole, 22.~ parts of
B-2-(bromomethyl)-4-(o~chlorophenoxymethyl)-2-(2,4-di-
chlorophenyl)-1~3-dioxolane, 4 parts o~ potassium lodide,
and 150 parts of dimethylformamide is stlrred and refluxed
~or 3 days. The reaction mixture is allowed to cool to room
temperature, poured into water and the product ls extracted
twice wlth dlisopropylether. The combined extracts are
washed twice with water, dried, ~iltered and evaporated.
The residue ls purified by column-chromatography over
~ilica gel using chloroform as eluent, y~elding two
fractions.
The first fraction is evaporated and the residue Or
A-1-[4-( -chlorophenox~methyl)-2-(2,l1-dichlorophenyl)-1,3- ;
di~xolan-2-ylm~thyl]imidazole is dissolved ln a mixture of
4-methyl-2-pentanone and dl~sopropylether. The solution
iB acidified with an excess of a ~oncentrated nitrlc acid
.
solution. The nitrate salt is filtered off and crystallized
rrom a mixture o~ 4-methyl-2-pentanone and diisopropylether,
yleld~ng A-1-[4-~o-chlorophenoxymethyl)-2-(2,4-dichlorophenyl.)~
- 1,3-dioxolan-2-yl~nethyl]imidazole nltrate; mp. 1~6.2C.
-78- . -
- - ~ - r
- - ~
.
106~8'73
The second fraction is evaporated and the residue of
B-1-[4-(o-chlorophenoxymethyl)-2-(2,4-dichlorophenyl)-1,3~
.
dioxolan-2-ylmethyl]imidazole is dissolved in a mixture of
4-methyl-2-pentanone and diisopropylether. The solution is
acidified with an excess of oxalic acid. The oxalate salt is
filtered off and crystallized from 4-methyl-2-pentanone, yielding
4 parts of B-l-r4-(o-chlorophenoxymethyl)-2-(2,4-dichlorophenyl)-
1,3-dioxolan-2-ylmethyl]imidazole dioxalate; mp. 103.5C.
. .
Example I.X
Following ~he procedure of Example LIX and using
equivalent amounts of the appropriate starting materials,
the following imidazoles and imidazole acid addition salts `-
are prepared. Where only one isomer is listed, no second
fraction was obtained from chromatography.
~I
CH ~ 6
~ O o
~ ~ 2 ;
-,,
.'.'
',-., ~, .
~''''' "' '
:.
i
-79_
~:
- . - . , :.
'. ~ ', ' ' , ~'
', ~ ' `
.'
:
~65~73
Melting Point
Isomer 6 7 Acid Salt of Salt _
- A 2,4-tC1)2 2,6-(C1)2 HNO3 159
cis 2,4-(C1)2 2-Br HNO3 142.2
trans 2,4-tC1)2 2-Br 2(COOH)2 151.3
A 2,4-(C1)2 2,5-(CH3)2 HNO3 180.9
B 2,4-(C1)2 2,5-(CH3)2 1.5(COOH)2 142 7
~ A 2,4-(C1)2 2,4,6-(Cl)3 ~lNO3 181.6
i 2,4-(C1)2 2,4,~-(C1)3 2(COOH)2 143.9
A 2,4-(C1)2 2-Cl,4-C(CH3)3 HNO3 141.2
B 2,4-(C1)2 2-Cl,4-C(CH3)3 HN03 141 1
A 2,4-(C1)2 2,4,5-(C1)3 HNO3 196.1
B 2,4-(C1)2 2,4,5-(C1)3 1.5(COOH)2 173.6
cis 2,4-(C1)2 2,5-(Br)2,4-CH3 HN03 175.4
A 2,4-(C1)2 2-OC2H5 HNO3 117 7
A ~ B 2-Cl 4-Br HNO3 145.3
B 2-C1 4-Br HNO3 152.7
A 2-Br 4-Br HNO3 149.9
B 2-Br 4-Br HN03 169.3
A 2,4-(C1)2 2-Cl,6-CH3 HNO3 154.2
-80-
Example LXI
A mixture of 9.7 parts of lH-imidazole, 1205 parts of A + ~-
B 2-~bromomethyl)-4-(4-bromophenoxymethyl)-2-(4 methylphenyl)-
1,3-dioxolane, 3 parts of potassium iodide and 135 parts of N,N-
dimethylformamide is stirred and refluxed for 72 hours. The
reaction mixture is poured into water and the product is extracted
twice with l,l'-oxybisethane. The extract containing A-l-
[4-(4-bromophenoxymethyl)-2-(4-methylphenyl)-1,3-dioxolcm-2-
ylmethyl]-lH-imidazole is washed twice with water, and an
excess of a concentrated nitric acid solution and 292'-
oxybispropane are added. The formed salt is filtered off and
crystallized from a mixture of ethanol and 2,2'-oxybispropane,
yielding 5.6 parts of A 1-[4-(4-bromophenoxymethyl)-2-(4-
methylphenyl)-1,3-dioxolan-2-ylmethyl]-lH-imidazole nitrate;
mp. 175.5C.
Example LXII -
;, - .
~ollowing the procedure of Example LXI but substituting
for the A+B-2-(bromomethyl)-4-(4-bromophenoxymethyl)-2-(4-methyl-
phenyl)-1,3-dioxolane used therein equivalent amounts of A+B-2-(bromo-
methyl)-4-(4-bromophenoxymethyl)-2-(4-chlorophenyl)-1,3-dioxolane
and A+B-2-(bromomethyl)-4-(4-bromophenoxymethyl)-2-(4-bromophenyl~
1,3-dioxolane there are prepared A-1-[4-(4-bromophenoxymethyl)-2-(4- ;
chlorophenyl)-1,3-dioxolan-2-ylmethyl]-lH-imidazole and its nitrate
salt (mp. 158) and A-1-~4-(4-bromophenoxymethyl)-2-(4-bromophenyl)-
1,3-dioxolan-2-ylmethyl]-lH-imidazole and its nitrate salt (mp. 170.8).
5~73
Example LXIII
A mixture oE 7.9 parts of lH-imidazole, 11.5 parts of
A + B 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(4-phenylphenoxy-
methyl)-1,3-dioxolane, 4 parts of potassium iodide and 135 parts of
N,N-dimethylformamide is stirred and refluxed for 3 days. The
reaction mixture is poured onto water and the product is extracted
twice with l,l'-oxybisethane. The combined extracts are washed
with water, dried, filtered and evaporated. The residue is purified
by column-chromatography over silica gel, using trichloromethane
as eluent.
The first fraction is collected and the eluent is evaporated.
The residue is converted into the nitrate salt in 4-methyl-2-pentanone
and 2,2'-oxybispropane. The salt is filtered off and crystallized from
a mixture of ethanol and 2,2'-oxybispropane, yielding A * B 1-[2-(2,4-
- dichlorophenyl)-4-(4-phenylphenoxymethyl)-1,3-dioxolan-2-ylmethyl~-
lH-imidazole nitrate; mp. 187.9C.
The second fraction is collected and the eluent is evaporated.
The residue is crystallized from 4-methyl-2-pentanone, yielding trans-
1-[2-(2,4-dichlorophenyl)-4-(4-phenylphenoxymethyl)-1,3-dioxolan-
2-ylmethyl]-lH-imidazole; mp. 155.7C.
Example LXIV
A mixture of 6.8 parts of imidazole, 8.5 parts of B-2-(bromo-
methyl)-4-(p-chlorophenoxymethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane,
2 parts of sodium iodide and 100 parts of dimethylformamide is stirred
and refluxed for 36 hours. The reaction mixture is allowed to cool to
room temperature and poured into water. The product is extracted twice
with benzene. The combined organic layers are washed twice with water,
dried and the solvent is removed in vacuoO The residue is purified
by column-chromatography over silica gel using chloroform as eluent.
-82-
.
.. . .
- : . . : - . : . -
- , . ~ ,
``` ~06S15'7~
The pure fractions are collected and the eluent is evaporated. The -
residue of B-1-[4-(p-chlorophenoxymethyl)-2-(2,4-dichlorophenyl)- ;;-
1,3-dioxolan-2-ylmethyl] imidazole is converted into the oxalate
salt in 4-methyl-2-pentanone: upon the addition of diisopropylether,
the salt is precipitated. It is filtered off and crystallized from
4-methyl-2-pentanone, yielding 3.1 parts of trans-1-[4-p-chloro-
phenoxymethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-2-ylmethyl]-
imidazole sesquioxalate; mp. 101C.
Example_LXV
Following the procedure of Example LXIV there is
prepared: ~
B-1-[4-(2,4-dichlorophenoxymethyl)-2-(2,4-dichlorophenyl)-1,3- ~ -
dioxolan-2-ylmethyl]imidazole sesquioxalate; mp. 121.2C.
: .
by the reaction of B-2-(bromomethyl)-4-(2,4-dichlorophenoxy-
methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolate with imidazole. -
,~,
Example LXVI
A mixture of 8.6 parts of lH-imidazole, 11.3 parts oE
A-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(3,5-dimethylphenoxy-
methyl)-1,3-dioxolane, 4 parts of potassium iodide and 135 parts of
'
'~
:. '
-83-
-, ' .. - . ': ' -:' , . ~. ,' - :
~0~5!!3~3
N,N-dimethylacetamide is stirred and refluxed for 3 days. The
reaction mixture is poured on-to water and the product is extracted
twice with 2,2'-oxybispropane. The combined extracts are washed
twice with water and an excess of a concentrated nitric acid solution
is added. The formed nitrate salt is Eiltered off and crys~allized Erom
a mixture of 2-propanol and 2,2l-oxybispropane. The product is
filtered off again and recrystalliæed from 4-methyl-2-pentanone,
yielding A-l-[2-(2,4-dichlorophenyl)-4-(3,5-dimethylphenoxymethyl)-
1,3-dioxolan-2-ylmethyl]-lH-imidazole nitrate hydrate; mp. 122.6C.
Example LXVII
Following the procedure of Example LXVI and using equi-
valent amounts o~ the appropriate starting materials, the following
imidazoles and imidazole acid addition salts are prepared:
~N
CH2.~R6
--~ O O
Melting Point
Isomer R R Acid Saltof Salt
A 2-CH3-4-Cl 4-Br HN03 159.3C
A=cis 2-CH3-4-Br 4-Br HN03 164.3C
A=cis 3-Br 4-Br HN03 158.7C
A=cis 3-Br-4-CH3 4-Br HN03 201.1C
A=cis 4-CN 4-Br HN03 190.1C
_________~ _______________ __________________ ______________ _____------
-84-
~;' '.
~S~3
Isomer Acid Salt Melting Point
2,4-(C1)2 6 5 2 3 2 110.3C
A=cis 3,5-(C1~2 4-Br HN03 167.1C
A=cis 3-N02 4-Br HN03 148.8C
A=cis 2,4-(C1)2 2-N02 2(COOH)2 95.2C
B=trans 2,4-(C1)2 2-N02 (C001l)2 157.2C
B=trans 2,4-(C1)2 4-(C6~l5-CH2) (COOH)2 137C
A + B 2,4-(C1)2 2-(C6H5) HN03 109.3C
A + B 2,4-(C1)2 4-~CH3-CH(CH3)] HNO3 115.2C
A 2,4-(C1)2 4-[CH3-C(CH3)2] HN03 169.5C
A 2,4-(C1)2 3,5-(C1)2 3 2 136.7C
A 2,4-(C1)2 3-CH3,4-Cl HN03 142.8C
A 2,3,4-(Cl)3 4-Br HN03 174.4C
2,4-(C1)2 2-Br,4-CH3 HN03 137.1C
Exan~le LXVIII
A mixture of 42 parts of lH-imidazole, 63 parts of A~B-
4-([1,1'-biphenyl~-4-yloxymethyl)-2-(bromomethyl)-2-(2,4-di-
chlorophenyl)-1,3-dioxolane, 20 parts of potassium iodide and 675
parts of N,N-dimethylformamide is stirred and refluxed for 3 days.
The reaction mixture is poured onto water and the product is extracted
with 2,2'-oxybispropane. The extract is dried, filtered and evaporated
The residue is converted into the nitrate salt in 4-methyl-2-pentanone
and 2,2'-oxybispropane. The product is separated as an oil. The
supernatant phase is decanted and the residual oil solidifies on
triturating in 4-methyl-2-pentanone. The nitrate salt is filtered off
and crystallized from ethanol, yielding 5 parts of cis-1-[4-([1,1'-
biphenyl]-4-yloxymethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-2-yl
methyl]-lH-imidazole nitrate; mp. 186.5C.
-85-
- : , . ~ . . . . -: - , , : . , .
~6~i8~3
Exampl e LXIX
- .
Following the procedure of Example LXVIII and u~ing
cquivalent amounts of thc appropriatc starting material~, the
following compounds are preparcd:
cis-l -~-(2, 4-dichlorophenyl)-~-(2-metho~cyphcnoxymcthyl)-
1,3-dioxolan-2-ylmethyl~-lH-imidazole ethanedioate hemi-
hydr~te; rnp. 123, 6C; and
.
cis-l-~2-(2, 4-dichlorophenyl)-4-(4-iluoropheno'xymethyl)_l, 3-
dioxolan - 2 ~ ylm ethy~7- l H -imida zol e; mp . 1 0 6 . 7
Example LXX
'' '
''' .
A mixture of 6. ~ part~ of ll-~-imidazole, 10 part~ of A~B-
2-(bromomethyl)-4-(3-chloro-~, 1 '-bipheny~7-4-yloxymethyl)~2-(2, 4- ~::
dich1orophenyl)-1, 3-dioxolane and 135 parts of N, N-dimethylacetamide
i~ etirred and reflwced for 5 days, The r~action mixture ia allowed to
. cool to room temperature and poured onto water. The product is extracted
twic~ with 1, 1 '-oxybisctllane. The combined extracts are washed witll
water, dried, Iiltered and evaporated. Thc residue is crystallized from
4-methyl-2-pentanone, yielding 2. 2 parts ~22%) of trans-1-~-(3- ' ~ -
chloro~ bipheny~7-4-yloxymethyl)-2-(2, 4-dichlorophenyl)-1, 3-
dioxolan-2-ylmcthy~-lH-imidazole; mp. 140. 8C.
` 1 ~ .
,' ~ '
., ;
- B6- . ` '':: ' .
' ~ :
Example LXXI ~65~7~ ~
A mixture of 10.2 parts of lH-imidazole and 26.8 parts of
sodium methoxide solution 30% is stirred and refluxed for 15 minutes.
Then there are added 90 parts of N,N-dimethylformamide. The methanol -
is distilled off till internal temperature of about 130C. After the
addition of another 90 parts of N,N-dimethylformamide, 50 parts oE A~B-
4-([1,1'-biphenyl]-4-yloxymethyl)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-
1,3-dioxolane are added portionwise at about 100C. Upon completion,
stirring is continued for 5 hours at reflux temperature. The reaction
mixture is poured onto a mixture of water and methylbenzene. The organic
phase is separated and stirred with activated charcoal. The latter is
filtered ofE and the filtrate is evaporated. The residue is purified
twice by column-chromatography over silica gel using a mixture of tri-
chloromethane and 1% of methanol as eluent. The pure fractions are
collected and the eluent is evaporated. The residue is crystallized from
2-propanol, yielding 9.3 parts of cis-1-[4-([1,1'-biphenyl]-4-yloxy-
methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-2-ylmethyl]-lH-imidazole;
mp. 150.7C.
.
Example LXXII
.-.
A mixture of 17 parts of lH-imidazole, 27.4 parts of A+B-
4-([1,1'-biphenyl]-4-yloxymethyl)-2-(bromomethyl)-2-(3,4,5-trichloro-
phenyl)-1,3-dioxolane and 135 parts of N,N-dimethylacetamide is stirred
and refluxed for 5 days. The reaction mixture is cooled and poured onto
water. The product is extracted twice with l,l'-oxybisethane. The
combined extracts are washed with water, dried, filtered and evaporated.
The residue is purified by column-chromatography over silica gel using
trichloromethane as eluent. The first fraction is collected and the eluent
is evaporated. The residue is converted into the nitrate salt in 4-methyl-
-~ 2-pentanone and 2,2'-oxybispropane. The salt is filtered off and crystal
lized from a mixture of acetonitrile and 2,2'-oxybispropane, yielding 3
parts of cis~ 4-([1,1'-biphenyl]-4-yloxymethyl)-2-(3,4,5-trichlorophenyl)-
-87-
.. ~ :
~0651373
1,3-dioxolan-2-ylmethyl]-lH-imidazole nitrate; mp. 212.2C. The second
fraction is collected and the eluent is evaporated. The residue is
converted into the nitrate salt in 4-methyl-2-pentanone and 2,2'-oxybis-
propane. The salt is filtered off and crystallized from a ~ixture of
acetonitrile and 2,2'-oxybispropane, yielding 1.9 parts of trans-1-[4-
(El,l'-biphenyl]-4-yloxymethyl)-2-(3,4,5-trichlorophenyl)-1,3-dioxolan-
2-ylmethyl]-lH-imidazole nitrate; mp. 158C.
Example LXXIII
Following the procedure of Example LXXII and using equi-
valent amounts of the appropriate starting materials, the following
imidazoles and imidazole acid addition salts are prepared:
,
cis-l-[4-([1,1'-biphenyl]-4-yloxymethyl)-2-(4-bromo-2-chloro-
phenyl)-1,3-dioxolan-2-ylmethyl]-lH-imidazole; mp. 161.8C;
trans-1-[4-([1,1'-biphenyl]-4-yloxymethyl)-2-(4-bromo-2-chloro-
phenyl)-1,3-dioxolan-2-ylmethyl]-lH-imidazole; mp. 164.6C;
~. .
cis-1-[4-([1,1'-biphenyl]-4-yloxymethyl)-2-(2-naphthalenyl)-1,3-
dioxolan-2-ylmethyl]-lH-imidazole; mp. 152.6C;
-: .:. .
trans-1-[4-([1,1'-biphenyl]-4-yloxymethyl)-2-(2-naphthalenyl)-1,3- ~
.~ , . . .
dioxolan-2-ylmethyl]-lH-imidazole nitrate; mp. 230.6C;
cis-1-[4-([1,1'-biphenyl]-4-yloxymethyl)-2-(2,4,5-trichlorophenyl)-
1,3-dioxolan-2-ylmethyl]-lH-imidazole nitrate; mp. 199.2C, and ~ -;
trans-1-~4-(~1,1'-biphenyl]-4-yloxymethyl)-2-(2,4,5-trichlorophenyl)-
1,3-dioxolan-2-ylmethyl]-lH-imidazole; mp. 139.2C.
, . ~'
,
- -88-
~658~ -
Example LXXIV
~ mixture of 11.5 parts of lH-imidazole, 17.5 parts of A+B-2- -
(bromomethyl)-2-(2,4-dichlorophenyl)-4-(3,4,5-trichlorophenoxymethyl)-1,3-
- dioxolane, 3 parts of potassium iodide and 180 parts of N,N-dimethyl=
acetamide is stirred and refluxed over week-end. The reaction mixture is ~-
poured onto water and the product is extracted four times with l,l'-oxybis-
ethane. The combined extracts are washed a few times with water, dried,
filtered and evaporated. The oily residue is purified by column~chromato-
graphy over silica gel using trichloromethane as eluent. The ffrst fraction
(A~isomer) is co:Llected and the eluent is evaporated. The oily residue
- is converted into the nitrate sal~ in 4-methyl-2-pentanone. The salt
is filtered off and crystallized from a mixture of 4-methyl-2-pentanone
and 2,2'-oxybispropane, yielding, after drying 7.5 parts (40%) of cis-l-
[2-(2,4-dichlorophenyl)-4-(3,4,5-trichlorophenoxymethyl)-1,3-dioxolan-2-
ylmethyl]-lH-imidazole nitrate, hydrate; mp. 149.9C.
The second fraction (B-isomer) is collected and the eluent
is evaporated. The oily residue is converted into the nitrate salt in 4-
methyl-2-pentanone. The salt is filtered off and crystallized from a
mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding, after
drying, 6.2 parts (27%) of trans-1-[2-(2,4 dichlorophenyl)-4-(3,4,5-tri~
chlorophenoxymethyl)-1,3-dioxolan-2-ylmethyl]-lH-imidazole nitrate;
mp. 169.3C.
Example LXXV -
Following the procedure of Example LXXIV and using equivalent
amounts of the appropriate starting materials, the following imidazoles
and imidazole acid addition salts are prepared. When only one isomer is
listed, no second fraction was obtained from chromatography.
cis-1-[4-(2-chloro-5-methylphenoxymethyl)-2-(2,4-dichlorophenyl)-
1,3-dioxolan-2-ylmethyl]-lH-imidazole; mp. 131.7C;
-89-
-
' "
~(~6S873
trans~ -(2-chloro-$-methylphenoxymethyl) 2_(2, 4_
dichlorophenyl)-l, 3-dioxolan-~-ylmcthy~7-lH-imidazole ' ':
~esquiethanedioate; m~p 148. 7C;
A-l- 14~ 6-dibromo-2~naphthalenyloxy~methy~7-2.
~Z, 4-dichlorophcnyl)-1, 3-dioxolan-2-ylmethyl} -l H-
irnidazole nitrate; n-p. 1 79, 4 C;
A~ (2, 3.. dichlorophcnoxymethyi)-2-(2, 4-dichlorophenyl)_ -
1,3-dioxolan-2-ylmethy~7~1H-imidazole diethanedioate; `
mp, 151.1C; and ;
B-l w~-(2, 3-dichlorophenoxymethyl)-2-(2, 4-dichlorophenyl)- ~ :
1, 3 dioxolan-2-ylmethylJ-1H-imidazole ~e9quiethanedioate;
mp. 156. 3C
, . .:
Example LXXVI
- ,: .:
Follo~ving the procedure of Example LYII and using equi~
valent amounts o~ thc appropriate starting materials, the
following compound6 are prepared: ' - .
''' :' ,:
A+B~ (4-bromophenylthiomethyl3-2-(2, 4-dichlorophcnyl)-
1~3-dioxolan-Z-ylmethyl7-lH-imidazolenitrate; mp. 170C; and ~.
. A+B-l -L2--(2, 4-dichlorophenyl)-4-(phenylthiomethyl)_l, 3- . :dioxolane-Z-ylmethy~7-llH-imidazole nitratc; m~. 122. 3C. - -
:
.
- 9 O - ' ~
- . ~,,:
- : .
. . ~ .:
,'
'.
3L~36S87~ :
Exa~ple LXYVII
A mixture of 4.5 parts of lH-imidazole, 6.5 parts of A-
2-(bromomethyl)-4-(4-bromophenoxyme-thyl)-2-(2,3-dichlorophenyl)-1,
3-dioxolane and 125 parts of N,N-dimethylacetamide is stirred and
refluxed for 2 days. The reaction mixture is allowed to cool to
room temperature, poured onto water and the product is extracted
twice with l,l'-oxybisethane. The combined extracts are washed
twice with water and an excess of a concentrated nitric acid solution
is added. The formed nitra~e salt is filtered off and crystallized
from 4-methyl-2-pentanone, yielding 5 parts (68%) of cis-1-[4-
(4-bromophenoxymethyl)-2-(2,3-dichlorophenyl)~1,3-dioxolan-2-
ylmethyl]-lH-imidazole nitrate; mp. 138.9C.
Example LXXVIII ~ ;
Following the procedure of Example LXXVII and using
equivalent amounts of the appropriate starting materials, the
following imidazole acid addition salts are prepared:
cis-1-[4-(3-chloro-[1,1'-biphenyl~-4-yloxymethyl)-2-(2,4-dichloro-
phenyl)-1,3-dioxolan-2-ylmethyl]-lH-imidazole nitrate; mp. 171.1C;
cls-1-[4-([l,l'-biphenyl]-4-yloxymethyl)-2-(2-chloro-4-methoxy-
phenyl)-1,3-dioxolan-2-ylmethyl]-lH-imidazole nitrate; mp. 172.9C;
A+B-1-[2-(2,4-dichlorophenyl)-4-(phenylmethyl)-1,3-dioxolan~2-yl-
methyl]-lH-imidazole diethanedioate; mp. 117.1C;
A+B-1-{2-(2,4-dichlorophenyl)-4-[(4-fluorophenyl)thiomethyl]-1,3-
dioxolan-2-ylmethyl}-lH-imidazole diethanedioate; mp. 129.8C;
A+B-1-[4-(4-chlorophenylmethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-
2-ylmethyl]-lH-imidazole sesquiethanedioate; mp. 141.~C
--91--
~ ~;S873
.
A+B-1-[2-(2,4-dichlorophenyl-4-(4-methoxyphenylmethyl)-1,3-
; dioxolan-2-ylmethyl]-lH-imidazole diethanedioate; mp. 94.2C;
cis-2-[2-(2,4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)-1,3-
` dioxolan-4-ylmethoxy]benzonitrile nitrate; mp. 162.1C; and
cis-butyl 4-[2-(2,4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)-
1,3-dioxolan-4-ylmethoxy]benzoate nitrate; mp. 90.5C.
Example LXXIX
,
A mixture of 14.4 parts of lH-imidazole, 18.5 parts oE
A+B 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4 [2-(4-methoxy-
phenyl)ethyl]-1,3-dioxolane, 5 parts of potassium iodide and 135
parts of N,N-dimethylacetamide is stirred and refluxed for 2 days.
The reaction mixture is allowed to cool to room temperature and
poured onto water. The product is extracted twice with 2,2'-oxy-
bispropane. The combined extracts are washed with water, dried,
filtered and evaporated. The residue is converted into the ethane-
dioate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane. The ;
salt is filtered off and crystallized from a mixture of 2,2'-oxybis- ~`
propane and ethanol, yielding A + B 1-{2-(2,4-dichlorophenyl)- `
4-[2-(4-methoxyphenyl~ethyl]-1~3-dioxolan-2-ylmethyl}-lH-
imida~ole ses~uiethanedi~a~e mp. 130.7C.
',' -:
'` .:
.~
-92- ~
' '
' : .
.~
~16~873
Example LXXX
Following the procedure of Example LXXIX and using
equivalent amounts of the appropriate starting materials, the
following imidazoles and imidazole acid addition salts are prepared:
l-{4-[2-(4-chlorophenyl)ethyl]-2-(2,4-dichlorophenyl)-1,3-dioxolan-
2-ylmethyl}-lH-imidazole diethanedioate; mp. 131.9C.;
1-[2-(2,4-dichlorophenyl)-4-(2-phenylethyl)-:L,3-dioxolan-2-yl-
methyl]-lH-imidazole sesquiethanedioa~e; mp. 117.8C.; and
A + B 1-{2-(2,4-dichlorophenyl)-4-[2-(4-methylphenyl)ethyl]-1,3-
dioxolan-2-ylmethyl}-lH-imidazole sesquiethanedioate hydrate;
mp. 123.8C.;
1-{4-[2-(2-chlorophenyl)ethyl]-2-(2,4-dichlorophenyl)-1,3-
dioxolan-2-ylmethyl}-lH-imidazole nitrate; mp. 98.8C; :
1-~2-(2,4-dichlorophenyl)-4-[2-(2,4-dichlorophenyl)ethyl]-
1,3-dioxolan-2-ylmethyl}-lH-imidazole nitrate; mp. 158.1C;
and
A+B 1-{2-(2,4-dichlorophenyl)-4~[2-(2,4-dichlorophenyl)-
ethyl]-1,3-dioxolan-2-ylmethyl}-lH-imidazole nitrate; mp. 140.1C.
Example LXXXI
To a stirred sodium methoxide solution, prepared starting
from 3.8 parts of sodium in 40 parts of methanol, are added 11 parts
of lH-imidazole and 225 parts of N,N-dimethylformamide. The methanol
is distilled off till internal temperature of 150C. Then there are
added 19 parts of A+B-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-ethyl-1,
3-dioxolane and the whole is stirred and refluxed for 1 hour. The
-93-
. . , , , , - , , . ':
~5~73
reaction mixture Ls allowed to cool to room temperature and poured
onto water. The product is extracted three times with l,l'-oxybisethane.
The combined extracts are washed with water, dried, filtered and
evaporated. The residue is purified by column-chromatography over
silica gel using a mixture of trichloromethane and 1% of methanol as
eluent. The first fraction is collected and the eluent is evaporated.
The residue is converted into the nitrate salt in 2,2'-oxy'bispropane.
The salt is filtered oEf and crystallized from a mixture of 2-propanol
and 2,2'-oxybispropane, yielding 12 parts (56~) of A+B-1-~2-(2,4-di-
chlorophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-lH-imiclazole nitrate;
- mp. 149.1C.
Lxa le LXXXII
mp
To a stirred sodium methoxide solution, prepared starting
from 2.8 parts of sodium in 40 parts of methanol, are added 8 parts
of lH-imidazole and 225 parts of N,N-dimethylformamide. The methanol -
is distilled off till internal temperature of 150C. Then -there are
added 30 parts of A+B-2-(4-bromo-2-chlorophenyl)-2-(bromomethyl)-4-
- ethyl-1,3-dioxolane and stirring is continued for 1 hour at reflux
' temperature. The reaction mixture is cooled and poured onto water. -
The product is extrac-ted twice with 2,2'-oxybispropane. The combined
. .
~ extracts are washed with water, dried, filtered and evaporated. The
: ....................................................................... .
- residue is purified by column-chromatography over silica gel using a
~- mixture of tric'hloromethane and 2% of methanol as eluent. The pure
' fractions are collected and the eluent is evaporated. The residue is
~- ~ converted into the nitrate salt in 2,2'-oxybispropane. The salt is
-' filtered off and crystallized from a mixture of 4-methyl-2-pentanone
;; and 2,2'-oxybispropane, yielding 8.5 parts (26%) of A+B-1-[2-(4-
bromo-2-chlorophenyl)-4-ethyl-1,3-dioxolan-2-yl-methyl]-lH-imidazole
nitrate; mp. 162O2C.
'.
-94-
. ~'
37 ::
Example LXXXIII
FDllowing the procedure of Example LXXXII and using
equivalent amounts of the appropriate starting materials, the
following imidazole acid addition salts are prepared: ~;
¢~ ~
CH2 ~ Ar A~B
O
R ~
Ar ~ ¦ Acid Salt ~ Melting Point
2-Cl3C6C6H4C2~l5 ~ HHN~03 117 5C
4-CH -C6H4 C2H5 HN03 172.7C
2~3~4-(cl)3-c6H2 C2H5 HN03 176.4C
2-Br-C6H4 C2H5 HN03 135.3C
2~3-(cl)2-c6H3C2H5 HN03 140.3C
4-OC~l3-c6H4C22E~l5 HHN03 151 6C
2-CH -4-cl-C6H3C2H5 HN03 126.8C
2-cl-4-ocH3-c6H3C2H5 HN03 117.7C
3,4,5-(C1)3 C6H2 C2H5 ~ HN03 195.8C
2-naphthyl C2H5 ¦ HN03 195.1C
2-ocH3-4-cl-c6H3C2H5 HN03 ¦ 131.8C
2~4~5-(cl)3-c6H2 C2H5 HN03 180.1C
- 20 2~4-(cl)2-c6H3nC3H7 HN03 119.2C
2~4-(cl)2-c6H3n 4 9 ~1N03 128 3
2~4-(cl)2-c6H3nC5Hll H~03 . C
2~4-(cl)2-c6H36 13 HN03 99.4C
2,4~(Cl)2-C6H3nC7H15 2(COOH)2 131C
2,4-(Cl)2 C6H3nC8H17 2(COOH)2 132.8C
~ _ _
-95-
51! 3~73
Example LXXXIV
A mixture of 32 parts of 1-(2,4-dichlorophenyl)-2-(lH-imidazol-
l-yl)ethanone, 55 parts of 1,2 9 3-propanetriol, 35 parts of 4-methylbenzene-
sulfonic acid, 96 parts of butanol and 360 parts of dimethylbenzene is
stirred and refluxed for 5 days with water-separator. The reaction
mixture is cooled, washed with a potassium carbonate solution and with
water, dried, filtered and evaporated. The residue is dissolved in a
diluted ethanedioic acid solution. The resulting solution is ~ashed
twice with l,l'-oxybisethane. The aqueous phase is separated and
neutralized with potassium carbonate. The product is extracted with tri-
chloromethane. The extract is dried, filtered and evaporated. The
residue is purified by column-chromatography over silica gel using a
mixture of trichloromethane and 2% of methanol as eluent. The first
fraction is collected and the eluent is evaporated. The residue is
converted into the nitrate salt in 2,2'-oxybispropane. The salt is
- filtered off and crystallized from a mixture of 4-methyl-2-pentanone and
2,2'-oxybispropane, yielding 5.5 parts (9.8~) of A+B-1-[4-(butoxymethyl)- ~
2-(2,4-dichlorophenyl)-1,3-dioxolan-2-ylmethyl]-lH-imidazole nitrate; -
., :.'.-: .
mp. 101.8C. The second fraction is collected and the eluent is
evaporated. The residue is triturated in l,l'-oxybisethane. The pro-
duct is filtered off and crystallized from a mixture of 4-methyl-2- ~-
pentanone and petroleumether, yielding 9.75 parts of A~B-2-(2,4-dichloro-
phenyl)-2-(lH-imidazol-l-ylmethyl)-1,3-dioxolane-4-methanol; mp. 128.1C.
Example ~XXXV
A mixture of 7.7 parts of lH-imidazole, 8 parts of cis-2-
-. (bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane-4-methanol, 1 part
of potassium iodide and 180 parts of N,N-dimethylacetamide is stirred
and refluxed for 3 days. The reaction mixture is cooled and evaporated.
Then there are added 50 parts of water and 300 parts of trichloromethane
to the residue. The whole is washed three times with water, dried,
,, ~ .
-96-
'. : '
.. . . , .. , ,:
.. . . - .. . -
`` 3L~ 3
filtered and evaporated. The residue is purified by column-chromato-
graphy over silica gel using a mixture of trichloromethane and 2% of
methanol as eluent. The pure fractions are collected and the eluent
is evaporated, yielding 9.2 parts of _ -2-(2,4-dichlorophenyl)-2-~lH-
imidazol-l-ylmethyl)-1,3-dioxolane-4-methanol; mp. 140C.
Example LXXXVI
Following the procedure of Example LXXXV and using an
equivalent amount of trans-2-(bromomethyl)-2--(2,4-dichlorophenyl)-1,3-
dioxolane-4-methanol as a starting material, there is obtained:
trans-2-(2,4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)-1,3
dioxolane-4-methanol; mp. 129C.
:, ~
Example LXXXVII
To a stirred mixture of 4 parts of cis-2-(2,4-dichlorophenyl)-
2-(lH-imidazol-l-ylmethyl)-1,3-dioxolane-4-methanol, 2.2 parts of
iodomethane and 90 parts of N,N-dimethylformamide are added 0.5
parts of sodium hydride dispersion 78%. Stirring is continued for 2
hours at room temperature. The reaction mixture is poured onto water ~-
and the product is extracted three times with l,l'-oxybisethane. The
combined extracts are washed with water and acidified with a nitric
acid solution in l,l'-oxybisethane. The formed nitrate salt is filtered
off and crystallized from 4-methyl-2-pentanone, yielding 2.2 parts
(45%) of _ -1-E2-(2,4-dichlorophenyl)-4-(methoxymethyl)-1,3-
dioxolan-2-ylmethyl]-lH-imidazole nitrate; mp. 140C.
-97-
. .
-
73
Example LXXXVIII
To a stirred mixture of 4 parts of CiS-2- (2, 4-dichlorophenyl)-
2-(lH-imidazol-l-ylmethyl)-1,3-dioxolane-4-methanol, 1.7 parts of
bromoethane and 90 parts of N,N-dimethylformamide are added 0.5 parts
of sodium hydride dispersion 78%. The whole is stirred for 1 hour at
room temperature. The reaction mixture is poured onto water and the
product is extracted three times with 2,2'-oxybispropane. The combined `
extracts are washed with water and acidi~ied with a nitric acid solution
in 2,2'-oxybispropane. The formed nitrate salt is filtered ofE and
crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybis- ~;~
propane, yieldin~ 4.7 parts (93%) of cis-1-[2-~2,4-dichlorophenyl)-4-
(ethoxymethyl)-1,3-dioxolan-2-ylmethyl]-lH-imidazole nitrate; mp. 134.7C. ~;
Example LXXXIX
::`
Following the procedure of Example LXXXVIII and using an
equivalent amount of an appropriate bromoalkane or bromoalkene `~
in place of the bromoethane used therein, the following imidazole
; acid addition salts are prepared:
cis-1-[2-(2,4-dichlorophenyl)-4-(prop~xymethyl)-1,3-dioxolan-2-yl-
methyl]-lH-imidazole nitrate; mp. 131.7C;
cis-1-[2-(2,4-dichlorophenyl)-4-(pentyloxymethyl)-1,3-dioxolan-2-yl
methyl]-lH-imidazole nitrate; mp. 78.6C;
cis-1-~2-(2,4-dichlorophenyl)-4-(hexyloxymethyl)-1,3-dioxolan-2-
ylmethyl]-lH-imidazole nitrate; mp. 87.1C;
' ;" '
- cis-1-[2-(2,4-dichlorophenyl)-4-(heptyloxymethyl)-1,3-dioxolan-
2-ylmethyl]-lH-imidazole nitrate; mp. 80.7C;
-98-
.:
cis-1-[2-(2,4-dichlorophenyl)-4-(octyloxymethyl)-1,3-dioxolan-2-yl
methyl]-lH-imidazole nitrate; mp. 73.4C; and
cis-1-[2-(2,4 dichlorophenyl)-4-(2-propenyloxymethyl)-1,3-
dioxolan-2-ylmethyl]-lH-imidazole nitrate; mp. 116.3C. ~-
. ,
Example XC
To a mixture of 4 parts oE trans-2-(2,4-dichlorophenyl)-2-
~lH-imidazol-l-ylmethyl)-1,3-dioxolane-4-methanol, 1.7 parts of
bromoethane and 90 parts of N,N-dimethylformamide are added
0.5 parts oE sodium hydride dispersion 78% and the whole is stirred
for 2 hours at room temperature. The reaction mixture is poured onto
water and the product is extracted twice with 2,2'-oxybispropane.
The combined extracts are washed with water and taken up in 2,2'-
oxybispropane. The solution is acidified with nitric acid. The formed
nitrate salt is filtered off and crystallized from 4-methyl-2-pentanone,
yielding 3.5 parts (69%) of trans-1-[2-(2,4-dichlorophenyl)-4-(ethoxy-
methyl)-1,3-dioxolan-2-ylmethyl]-lH-imidazole nitrate; mp. 151.4C. -
,"~''':" ' '
Example XCI
To a stirred mixture of 2.5 parts of l-chloro-4-(chloro-
methyl~benzene, 4 parts of cis-2-(2,4-dichlorophenyl)-2-(lH-
imidazol-l-ylmethyl)-1,3-dioxolane-4-methanol and 90 parts of
N,N-dimethylformamide are added 0.5 parts of sodium hydride
dispersion 78%. Stirring is continued for 5 hours at room temperature.
The reaction mixture is poured onto water and the product is extracted
twice with 2,2'-oxybispropane. The combined extracts are washed
with water~ dried9 filtered and acidified with nitric acid. The
formed nitrate salt is filtered off and crystallized from a mixture
_99_
1(~6S~373
oE 4-methyl-2-pentanone and 2,2~-oxybispropane. The product is
filtered off and recrystallized from a mixture of 4-methyl-2-
pentanone and 2,2'-oxybispropane, yielding 3.5 parts (56%) of
cis-1-[4-(4-chlorophenylmethoxymethyl)-2-(2,4-dichlorophenyl)- :: '
1,3-dioxolan-2-ylmethyl]-lH-imidazole nitrate; mp. 131.7C.
Example XCII
By repeating the procedure of Example XCI alld ~lsing an
equivalent amount of an appropriate (chloromethyl)benzene ln place
of the l-chloro-4 (chloromethyl)benzene used therein, there are
obtained:
cis-1-{4-~(4-bromophenyl)methoxymethyl]-2-(2,4-dichlorophenyl)-1,3-
dioxolan-2-ylmethyl}-lH-imidazole nitrate; mp. 101.4C; and
cis-1-{2-(2,4-dichlorophenyl)-4-[(4-fluorophenyl)methoxymethyl]-
1,3-dioxolan-2-ylmethyl}-lH-imidazole nitrate; mp. 107C.
ExamRle XCIII
. : :
To a stirred mixture of 3.3 parts of 2,4-dichloro-1-(chloro-
methyl)benzene, 5 parts of A~B~2-(2,4-dichlorophenyl)-2-(lH-
imidazol-l-ylmethyl)-1,3-dioxolane-4-methanol and 90 parts of
N,N-dimethylformamide are added 0.5 parts of sodium hydride
20 dispersion 78% and stirring is continued~for 3 hours at room tempera-
ture. The reaction mixture i5 poured onto water and the product is
extracted three times with 2,2'-oxybispropane. The combined extracts
are washed with water, dried, filtered and evaporated. The residue
'- '~,
-100~
:, .,
;` ~ll~6SE~3
is purified by column-chromatography over silica gel using trichloro-
methane as eluent. The first fraction (A-isomer) is collected and the
eluent is evaporated. The residue is converted into the nitrate salt in
4-methyl-2-pentanone and 2,2'-oxybispropane. The salt is filtered off
and recrystallized from a mixture of 4-methyl-2 pentanone and 2,2'-
oxybispropane at 0C, yielding 2.9 parts (35%) of cis-1-{2~(2,4-dichloro-
phenyl)-4-[(2,4-dichlorophenyl)methoxymethyl]-1,3-dioxolan-2-ylmethyl}-
lH-imidazole nltrate; mp. 96.9C.
The second Eraction (B-isomer) is collected and the eluent
is evaporated. The residue is converted into the nitrate salt in 4-
methyl-2-pentanone and l,l'-oxybisethane. The salt is filtered off and
recrystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxy- `
bispropane, yielding 1.6 parts (19%) of trans-1-{2-(2,4-dichloro- i-
phenyl)-4-~(2,4-dichlorophenyl)methoxymethyl]-1,3-dioxolan-2-ylmethyl}-
lH-imidazole nitrate; mp. 131.9C.
Example XCIV
By repeating the procedure of Example XCIII and using an
equivalent amount of 4-(chloromethyl)-1,1'-biphenyl in place of the
2,4-dichloro-1-chloromethylbenzene used therein, there are obtained:
cis-1-[4-(~1,1'-biphenyl]-4-ylmethoxymethyl)-2-(2,4-dichlorophenyl)-
1,3-dioxolan-2-ylmethyl]-lH-imidazole diethanedioate; mp. 107.6C; and
trans-1-[4-([1,1'-biphenyl]-4-ylmethoxymethyl)-2-(2,4-dichlorophenyl)-
1,3-dioxolan-2-ylmethyl]-lH-imidazole nitrate; mp. 168C.
Example XCV
A mixture of 2.2 parts of (4-hydroxyphenyl) phenyl methanone,
4.2 parts of cis-2-(2,4-dichlorophenyl)-2-~lH-imidazol-1 ylm2thyl)
--101--
~)6~87~3 ~
1,3-dioxolan-4-ylmethyl methanesulEonate, 2 parts of potassium carbo-
nate and 68 parts oE N,N-dimethylformamide is stirred over-night at
100C. The reaction mixture is cooled and poured onto water. The
product is extracted twice with l,l'-oxybisethane. The combined ex-
tracts are washed with water, dried, filtered and evaporated. The
residue is converted into the nitrate salt in 4-methyl-2-pentanone and
2,2'-oxybispropane, yieldin~ 4.5 parts (78%) of cis-{4-[2-(2,4-di-
chlorophenyl)-2-(1~1-im:Ldazol-l~ylmethyl)-:L,3-clloxo:lan-ll-y:LmeLhoxy~-
phenyl}phenyl methanone nitrnte; mp. 179C.
Example XCVI
Following the procedure of Example XCV and using an equi-
valent amount of an appropriate phenDl in place of the (4-hydroxy-
methyl) phenyl methanone used therein, the following imidazoles and
imidazole acid addition salts are prepared: `
-.:
cis-5-chloro-2-[2-(2,4-dichlorophenyl)-2-(lH-imidazol-l-yl-
methyl)-1,3-dioxolan-4-ylmethoxy]-4-methylphenyl phenyl
methanone ethanedioate; mp. 170.8C;
cis-methyl 4-[2-(2,4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)-l,
3-dioxolan-4-ylmethoxy]benzoate nitrate; mp. 167.8C;
~ ` ' '
cis-{2-[2-~2,4-dichlorophenyl)-2-~lH-imidazol-l-ylmethyl~-1,3-
dioxolan-4-ylmethoxy]-5-methylphenyl}phenyl methanone nitrate;
mp. 145.4C;
cis-(4-chlorophenyl){2-[2-(2,4-dichlorophenyl)-2-(lH-imidazol-
l-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-4-methoxyphenyl}methanone;
mp. 168.3C;
,~',~ " '
-102- ~
.. .. .
1~5873
cis-{2-[2-(2,4-dichlorophenyl)-2-(lH-imidazol l-ylmethyl)-1~3-
dioxolan-4-ylmethoxy]-4-methoxyphenyl}phenyl methanone;
mp. 149.2C;
cis-1-{2-(2,4-dichlorophenyl)-4-[3-(trifluoromethyl)phenoxymethyl]- '
1,3-dioxolan-2-ylmethyl}-lH-imidazole nitrate; mp. 152.6C;
cis-l-{4-[2-(2,4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)-
1,3-dioxolan-4-ylmethoxy]phenyl}ethanone nitrate; mp. 182.6C;
cis-methyl 2-[2-(2, 4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)-
- 1,3-dioxolan-4-ylmethoxy]benzoate nitrate; mp. 140.5C; and
cis-1-{4-[2-(2,4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)-
1,3-dioxolan-4-ylmethoxy]phenyl}-1-propanone nitrate; mp. 176.2C.
Example XCVII
A mixture of 12.5 parts of 1,2-butanediol, 19 parts of 1-(2-
. .
chloro-4-fluorophenyl)-2-(lH-imidazol-l-yl)ethanone hydrochloride,
16 parts of 4-methylbenzenesulfonic acid, 40 parts of l-butanol and
225 parts of dimethylbenzene is stirred and refluxed for 6 days with
water-separator. After cooling, the reaction mixture is filtered and
the filtrate is washed with a diluted sodium hydroxide solution and
with water. After the addition of 2,2'-oxybispropane, the whole is
acidified with a nitric acid solution. The formed nitrate salt is
filtered off and crystallized from a mixture of 4-methyl-2-pentanone
and 2,2'-oxybispropane, yielding 5.7 parts (22%) of A+B-1-~2-(2-
chloro-4-fluorophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-lH~imidazole
nitrate; mp. 132.4C.
-103-
1~65~73
`:
Example XCVIII
~ ollowing the procedure of Example XCVII and using equi-
valent amounts of the appropriate starting materials, the following
imidazoles and imidazole acid addition salts are prepared:
A+B-1-[2-(4-bromophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-
lH-imidazole nitrate; mp. 194.7C;
A~B-1-[2-(2,4-dibromophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]- ;
lH-imidazole nitrate; mp. 149.7C;
A~B-1-[4-ethyl-2-(2-thienyl)-1,3-dioxolan-2-ylmethyl]-lH-imidazole
nitrate; mp. 135.4C;
A+B-1-[2-(5-chloro-2-thienyl)-4-ethyl-1,3-dioxolan--2-ylmethyl]-
lH-imidazole nitrate; mp. 164.3C;
A+B-1-[4-(chloromethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-2-yl-
methyl}lH-imidazole nitrate; mp. 166.1C;
A+B-1-[4-([1,1'-biphenyl]-4-ylmethyl)-2-(2,4-dichlorophenyl)-1,3-
dioxolan-2-ylmethyl]-lH-imidazole diethanedioate; mp. 116.8C; -
A+B-1-[2-(2,4-dichlorophenyl)-4-(4-fluorophenylmethyl)-1,3-
dioxolan-2-ylmethyl]-lH-imidazole sesquiethanedioate; mp. 153.1C;
: . . . .
~ A+B-1-{2-(2,4-dichlorophenyl)-4-[(4-methylphenyl)methyl]-1,3-
- 20 dioxolan-2-ylmethyl}-lH-imidazole sesquiethanedioate; mp. 123.1C;
A+B-1-~4-(4-bromophenylmethyl)-2-(2,4-dichlorophenyl)-1,3-
dioxolan-2-ylmethyl]-lH-imida201e diethanedioate; mp. 128.8C; ~
:.
''''' ,~ '
": ~
',''' ,~
'
-104~ ~
. .
- : ' : , ,: - , ~- :
`` 3L~6~ 73
.
A~B-1-{4-[2-(~1,1'-biphenyl~-4-yl)ethyl]-2-(2,4-dichlorop~enyl)-
1,3-dioxolan-2-ylmethyl}-1~-imidazole sesquiethanedioate hemi-
` hydra~e; mp. 143.9C; and
A+B-1-{2-(2,4-dichlorophenyl)-4-[2-(phenylmethyl)phenoxymethyl~-
1,3-dioxolan-2-ylmethyl}-L~-imidazole sesquiethanedioate hemi-
hydrate; mp. 113C.
ExamF,le IC
A mixture of 13.8 parts o 1-(2-chloro-4-fluorophenyl)-2-
(lH-imidazol-l-yl)ethanone hydrochloride, 14.6 parts of 3-(~1,1'-
biphenyl]-4 yloxy)-1,2-propanediol, 16 par~s of 4-methylbenzene-
sulfonic acid, 40 parts of butanol and 22S parts of dimethylbenzene
is stirred and refluxed for one week with water-sepsrator. After
cooling, l,l'-oxybisethane is addet and the whole is washed
successively with a diluted sodium hydroxide solution and with water,
dried, filtered and evaporated. The residue is purified by column-
chromatography over silica gel using trichloromethane as eluent.
The first fraction (A-isomer) is collected and the eluen~ is evaporated.
The residue is converted into the nitrate salt in 4-methyl-2-pentanone
and 2,2'-oxybispropane. The product is filtered off and crystallized
from a mixture of acetonitrile and Z,2' oxybispropane, yielding
5 parts of cis-1-~4-([1,l'-biphe~y~ -4-yloxymethyl)-2-(2-chloro-
4-fluorophenyl)-1,3-dioxolan-2-ylmethy~ -lH-imidazole nitrate;
mp. 185.7C.
The second fraction (B-isomer) is collected and the eluent
is evaporated. The residue is con~erted into the nitrate salt in 4-
methyl-2-pentanone and 2,2'-oxybispropane. The salt is filtered off
and crystallized from a mixture Of acetonitrile and 2,2'-oxybispro-
pane, yielding 5.9 parts of tra _-1-[ 4-([1~1r -biphenyl]-4-yloxymethyl)-
2-(2-chloro-4-fluorophenyl)-1,3-dioxolan-2-ylme~hyl]-1~-imidazole
nitrate; ~p. 156.9C.
-105-
8'73
Example C
FollowLng the procedure of Example IC and using equivalent
amounts ~ the appropriate starting materials, the following imidazoles
and imidazole acid addition salts are prepared. When only one isomer
is listed, no second fraction was obtained from chromatography.
cis~ [4-([1,1'-biphenyl]-4-yloxymethyl)-2-(2-thienyl)~1,3-
dioxolan-2-ylmethyl]-lH-imidazole; mp. 149.5C; -;
trans-1-[4-([1,1'-biphenyl~ -y:Loxymethyl)-2-(2-thienyl)-1,3-
dioxolan-2-ylmethyl]-lH-imidazole; mp. >300C;
0 ci9-1- ~4-( [1,1~-biphenyl]-4-yloxymethyl~-2-(2,4-dibromophenyl)-
1,3-dioxolan-2-ylmethyl}-lH-imidazole nitrate; mp. 174.4C;
trans-l-[4-([1,1'-biphenyl]-4-yloxymethyl)-2-(2,4-dibromophenyl)-
1,3-dioxolan-2-ylmethyl]-lH-imidazole nitrate; mp. 141.8C-, and
cis-1-[4-([1,1~-biphenyl]-4-yloxymethyl)-2-(5-chloro-2-thienyl)-
1,3-dioxolan-2-ylmethyl]-lH-imidazole nitrate; mp. 170C.
'
Example CI
To a stirred mixture of 1.1 parts of 3-chloro-1-propyne,
4 parts of cis-2-(2,4-dichlorophenyl)-2-(lH-imidazol-l-ylmethyl)-
1,3-dioxolane-4-methanol and 90 parts of N,N-d-imethylformamide
are added 0.5 parts of sodium hydride dispersion 78%. Stirring is
continued for 3 hours at room temperature. The reaction mixture ;
is poured onto water and the product is extracted twice with 1,1'
.: ~. , .
oxybisethane. The combined extracts are washed with water~ dried,
: ~'. ~ .
-106-
,:~
filtered and evaporated. The residue is purified by column-chromato-
graphy over silica gel using a mixture of trichloromethane and methanol
(98:2) as eluent. The pure fractions are collected and the eluent is
evaporated. The residue is converted into the ethanedioate salt in
4-methyl-2-pentanone and 2,2'-oxybispropane. The salt is filtered
off and crystallized from 4-methyl-2-pentanone, yielding 3.6 parts
(55%) of cis=1~[2-(2,4-dichlorophenyl)-4-(2-propynyloxymethyl)-1,3-
dioxolan-2-ylmethyl]-lH-lmldazole dlethanedLoa~e; mp. L45.6C.
Example CII
A mixture of 17 parts of lH-imidazole, 16 parts of A+B-
2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-ethenyl-1,3-dioxolane
and 225 parts of N,N-dimethylformamide is stirred and refluxed
for 3 days. The reaction mixture is cooled, poured onto water and
the product is extracted twice with l,l'-oxybisethane~ The combined
extracts are washed with water, dried, filtered and evaporated. The
residue is purified by column-chromatography over silica gel using
trichloromethane as eluent. The pure fractions are collected and the
eluent is evaporated. The residue is converted into the nitrate salt
in 4-methyl-2-pentanone and 2,2'-oxybispropane. The salt is
filtered off and crystallized from 4-methyl-2-pentanone, yielding
2.4 parts (13%) of A+B-1-[2-~2,4-dichlorophenyl)-4-ethenyl)-
1,3-dioxolan-2-ylmethyl]-lH-imidazole nitrate; mp. 150.9C.
-107-
.
. .
~ : . . , :
