Note: Descriptions are shown in the official language in which they were submitted.
Case 900-9373
NEW AZOLES, PROCESSE5 FOR THEIR PREPARATION AND THEIR USE
The present invention concerns l-phenyl-2-azole-ethylam;nocarbonyl-
derivativesg processes for their production, compositions containing them
and their use as pharmaceuticals e.g. as anti-mycotics and as agrochemicals
e.g. as fungicides.
In particular the invention concerns compounds of formula I
R
,1
CH2 -CH-N-C-R2
~0
~ .
wherein R3 R4
Rl and R2 represent independently an optionally substituted aliphatic
heteroaryl or aryl group or Rl may also represent hydrogen~ R3 and R4 repre-
10 sent hydrogen, halogen, nitro, an optionally substituted aliphatic group
which is optionally attached via S, O, SO or SO2, or optionally substituted
phenyl or phenoxy and X represents N or CH; in free form or in the form of
an acid addition salt.
More particularly the invention concerns compounds of formula I
15 wherein Rl and R2 represent independently, alkyl, cycloalkyl, cycloalkyl-
alkyl, alkenyl or optionally substituted aralkyl, aralkenyl,
heteroaryl or aryl or Rl may also represent hydrogen,
R3 and R4 represent independently, hydrogen, halogen, nitro,
optionally mono- or poly-halogen or-phenyl substituted lower
2n alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower
alkylsulphinyl, lower alkylsulphonyl or lower alkoxy or
optionally substituted phenyl or pheno~y, and
X represent N or CH;in free form or in acid addition salt form.
Preferred compounds of formula I are those
~3L242~2~
wherein -2- 900-9373
Rl represents hydrogen or alkyl,
R2 represents alkyl, cycloalkyl1 cycloalkylalkyl or alkenyl or aralkyl,
aralkenyl, heteroaryl or aryl each of which may be unsubstituted or mono-
or poly-substituted by halogen, cyano, trifluoromethyl, lower alkyl, lower
alkynyl, lower alkoxy, optionally acyl bearing lower amino, alkylamino or
dialkylamino, cyclic amino optionally containing a second heteroatom and
optionally acylated, phenyl9 phenoxy or heteroaryl whereby any cyclic amino,
phenyl, phenoxy, lower alkynyl or heteroaryl optionally present
as a substituent may itself in turn be substituted by a further group as
R2 or R3.
R3 and R4 represent independently hydrogen or halogen and
X represents N or CH;in free form or in acid addition salt form.
Alkyl moieties present in or as substituents pre~erably contain 1 to
10, especially 1 to 7 carbon atoms. Lower alkyl groups preferably contain
1 to 4 carbon atoms, lower alkenyl and alkynyl preferably 2 to 4. Bridging
alkyl groups contain e.g. 1 to 4 preferably l or 2 carbon atoms, bridging
alkenyl groups may contain 2 to 4 especially 2 carbon atoms. Cycloalkyl
pre~erably contains 3 to 6. Aryl preferably stands for phenyl. Heteroaryl
preferably contains 5 or 6 ring members and may represent e.g. pyridyl or
thienyl. When R2 stands ~or unsubstituted aryl this may be e.g. phenyl or
naphthyl. Unsubstituted aralkyl and aralkenyl are preferably phenalkyl
and phenalkenyl respectively. Heteroaryl contains pre~erably 5 or 6 rin~
members and as heteroatoms one or more sulphur or nitrogen atoms and stands
for e.g. thienyl or pyridyl. Aryl, aralkyl, aralkenyl and heteroaryl may
also be mono- or poly substituted. Examples of suitable substituents are
halogen such as chlorine, bromine, iodine and fluorine; Cl 4alkyl
especially methyl; amino which may optionally be substituted by one or
two alkyl9 especially methyl, groups, in particular dimethylamino; or
30 phenyl. A cyclic amino group, which may con~ain a second heteroatom e.g.
nitrogen; or a he~erocycle may each also serve as substituents. All these
substituents (on R2) may in turn be^further substituted by the substi-
tuent groups mentioned above.
7~3
-3- 900-9373
R3 and R4 may be for example halogen, mono- or poly-, halogen or
phenyl-substituted lower alkyl, lower alkenyl, lower alkynyl, lower
alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or lower alkoxy or
optionally substituted phenyl- or phenoxy; preferably halogen or hydrogen.
A particular compound group is that wherein in formula I
Rl and R2 independently represent alkyl~ cycloalkyl, cycloalkylalkyl,
aralkyl, alkenyl, aralkenyl, heteroaryl or aryl whereby heteroaryl and
aryl may be optionally substituted, or for Rl also hydrogen.
R3 and R~ independently represent hydrogen, halogen, nitro optionally
mono- or poly-halogen substituted lower alkyl, lower alkenyl, lower alkynyl,
lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or lower
alkoxy or optionally substituted phenyi or phenoxy and
X represents N or CH;in free form or in acid addition salt form.
The compounds of formula I may be prepared according to the invention
by acylating a compound of formula II
X~lN ~ R,l I I
CH2 - CH - NH
R ~ 4
wherein Rl, R3, R4 and X are as defined above.
The reaction may for example be carried out in conventional manner
by reacting a compound of formula II with the acid halide of the
appropriate R2 bearing group in a solvent such as e.g. an organic or
inorganic base which may at the same time act as an acid binding agent,
such as pyridine and optionally with addition of an acylation accelerator
such as 4-dimethyl aminopyridine. The reaction may also be carried out
~2~t~Z3
-4- 900-9373
by reacting a compound of for~ula II with an active ester of the R2
bearing acid. The reaction can thus for example be carrled out with
a pyridyl-2-thiolester in an inert solvent such as a di-lower alkyl
carboxylic acid amide such as dimethylformamide at room temperature.
The end products may be isolated and purified in conventional manner
and recovered in free form or in the form of an acid addition salt.
The starting materials of formula II are in part new and may be
prepared by
a) when Rl is other than hydrogen especially alkyl, converting a compound
of formula III
CH2 - C = O I I I
R3 R4
to the corresponding Schiff's base of formula IV
~,~
X`N IV
CH2 - C - NRl'
R3 R4
which is then reduced, or
b) when Rl = hydrogen reacting a compound of formula V
Il - N
N~ V
CH - CH - Y
R3 R4
~;24~23
-5- 900-9373
with an azide e.g. LiN3 and reducing the compound of formwla VI thus
obtained
N VI
CH2 ~ N3
whereby in the formulae IIIto VI; X, R3 and R~ are as de~ined above, Rl'
has the same meaning as Rl except for hydrogen and is especially alkyl and
Y is halogen especially chlorine.
These processes are carried out in conventional manner e.g. as
described in the examplesO The products may be isolated and purified in
conventional manner or directly further reacted as appropriate.
The intermediates of formula III and V and the acylating a~ents
are known or may be prepareJ analogously to knowm methods and/or
analogously to the examples herein2fter.
The compounds of formula I exhibit chemotherapeutic, in particular
anti-mycotic activity as indicated in ~itro on mycelial forms of candida
albicans in series dilution tests analogous to J. Yan Cutscm et al.
(Mykosen~ 24~ 596-602, 1981~ at concentrations of ca. 0.05 to 12.0 ug/ml
anJ in vivo against intravaginal Candida albicans infestions in rats
followiny systemic, peroral use at dosages of ca. 1 ts 25 mg/kg animal
body weight.
3L~ 2~ 3
-6- 900-9373
The compounds are therefore indisated for use as pharmaceuticals
particularly as anti-mycotics.
An indicated suitable daily dosage for use as an anti-mycotic is
~rom 70 to 2000 mg. I~ desired this may be administered in divided doses
2 to 4 times a day in unit dosage ~orm containing about 17.5 to 1000 mg
of the compound or in sustained release form.
The compounds may be used in free base form or in the form of
chemotherapeutical`ly acceptable acid addition salts e.g. as the hydro-
chloride, hydrogen fumarate or naphthalin-1,5-disulfonate. Such salt
forms exhibit the same order of activity as the free base forms.
The compounds may be admixed with conventional chemotherapeutically
acceptable diluents and carriers, and, optiona11y other excipients and
administered orally, topically, i.v. or parenterally in such forms as
tablets, capsules, creams, tinctures or injectable preparations.
Such compositions also form part of the invention.
The invention therefore also concerns a method of combatting
infections and diseases caused by mycetes comprising administering to a
subject in need of such treatment an effestive amount of a compound of
formula I or a chemotherapeutically acceptable acid addition salt thereof
-7 900-9373
and such compounds for use as chemotherapeutic agents, in particular as
anti-mycotic agents.
The compounds of the invention in free ~orm or in agriculturally
acceptable salt or metal complex form are also suitable ~or combatting
phytopathogenic fungi. This fungicidal activity can be demonstrated i.a.
in in vi~o tests against Uromyces appendiculatus (bean rust) on runner
beans as well as against other rust fungi (e.g. Hemileia, Puccinia) on
coffee, wheat, flax and ornamentals (e.g. pelargonium, snapdragon); and
against Erysiphe cichoracearum on cucumber as well as against other
powdery mildews (e.g. E. graminis f. sp. tritici. E. gram. f. sp. hordei,
Podosphaera leucotricha, Uncinula recator) on wheat, barley, apple and
vines.
Preferred substituent meanings are
for Rl = a) hydrogen
or b) lower alkyl, especially methyl
for R2 = a) straight chain or branched alkyl especially with
1 to 7 carbon atoms
b) aralkyl especially phenalkyl which may be optionally
substituted
c) aralkenyl especially phenalkenyl
d) heteroaryl preferably with 5 or 6 ring members and
S and/or N as heteroatom(s)
e) unsubstituted aryl especially phenyl or naphthyl
~) aryl (especially phenyl) mono- or poly-substituted by
halogen, lower alkyl, amino or dialkylamino
g) aryl substituted by phenyl which itself may be mono- or
poly-substituted by halogen, lower alkyl, amino or
dialkylamino
h) aryl substituted by a cyclic amino group whlch may
contain a second heteroatom e.g. nitrogen and which itself
may be substituted by aminoacyl (including mono- or di-
alkylamino), aracyl, alkanoyl, aralkyl, or alkyl,
~Z'~
-8- 900-9373
i) aryl substituted by heteroaryl
j) aryl substituted by alkynyl which itself may be substi-
tuted by aryl,
for R3 and R4 independently a) hydrogen
or b) halogen,
for X = a) N
b) CH.
Especially preferred are combinationsof the particular substituent
meanings mentioned hereinbefore.
A particularly preferred compound group is that comprising compounds
of formula I wherein
Rl represents hydrogen
R2 represents Cl 7alkyl 9 unsubstituted phenyl or naphthyl, unsubsti-
tuted heteroaryl with 5 or 6 ring members and S or N as heteroatom(s),
15 unsubstituted or halogen substituted phen-(Cl 43-alkyl, unsubstituted
or halogen substituted styryl, phenyl mono- or poly-substituted by
halogen, lower alkyl9 or dialkylamino, phenyl substituted by phenyl
itself optionally substituted by halogen, lower alkyl or dialkylamino,
phenyl substituted by a cyclic amino group which may contain as a second
~0 heteroatom nitrogen and which itself may be substituted by phenalkyl,
phenacyl, phenyl, aminoacyl (including mono- or di-alkylamino) or alkyl,
heteroaryl substituted phenyl or phenalkynyl substituted phenyl.
R3 and R4 represent hydrogen or halogen and
X stands for N or CH;in free base form or in the form of an acid
addition salt.
Particularly preferred within this group are compounds wherein R2
is substituted phen~l.
The following examples illustrate the invention, temperatures being
in degrees celcius.
9_ 900-9373
Example 1 : N-Pivalo~ 2~4-dichlorophen~1)-2-(lH-imidazol-l-~
.
eth~lamine
_ _
1 g of 1-(2,4-dichlorophe~yl)-2-(lH-imidazol-l-yl)ethylamine are
dissolved in pyridine, mixed with 470 mg pivaloylchloride and if desired
l-equivalent of 4-dimethylaminopyridine and stirred at room temperature
until completion of reaction (ca. 1 hour). The solvent as removed by
rotation under vacuum, the residue partitioned between water and
methylene chloride and the organic phase washed, dried and evaporated
under rotation. The crude title compound is purified by crystallisation
10 from isobutylmethyl ketone/diisopropylether and is obtained as colourless
crystals, m.p. 84-88.
Example 2 : N-54-(4-Chloroehenyl)benzoyl2-1 (2,4-d_chloroehenyl)-2-(lH
imidazol-l-yl)ethylamine
1.6 g of 4-(4-chlorophenyl)benzoic acid pyridyl-2-thiolester and
1.26 9 of 1-(2,4-dichlorophenyl)-2-(lH-imidazol-l-yl)ethylamine are
stirred at room temperature with 50 ml o~ dimethylformamide until
completion of reaction (ca. 1 hour). The solvent is removed under vacuum
and the residue partitioned between methylene chloride and aqueous
NaHC03. The organic phase is washed, dried and concentrated under
vacuum and the residue crystallised from ethanol. Colourless crystals are
obtained m.p. 246-250.
The following compounds may be obtained analogously to Examples 1
and 2.
~ . . __ ~ .
Ex Rl R~ R3 _ R4 X m.p.
3 H ^C(CH3)3 2-CI 4-CI N 139-140
4 CH3 ~ 2-CI 4-CI N 144-145
H C6H5 2-CI 4-CI N 21a-220O
6 H ~ Cl 2-CI 4 Cl CH lEE-I9l
~Z~ Z3
- 10 - 9OC-9373
_ _ . . . ~ ,
E x . R 2 R3 R4 X m . p .
7 CH3 , 2-CI 4-CI CH oi 1
8 H-CH=CH_.~\ //. 2-CI 4^CI CH 170-173
9 H \\_// 3 H H CH 195 -196
H ~ F H H CH 195 D
11 H !~S I ! H H CH 205-206
12 H ~ - ; H H CH 166-167
13 H (CH2) 2~ H H CH 151 -152
14 H -CH (CH3) 2 H H CH 191-194
H _ / - \ H H CH 152 - 154
16 CH3 ~ Cl 2 -CI 4 -CI CH 157 - 1 j8
17 H \~ 13 2-CI 4-CI CH 214
18 H - I~SI I 2-CI 4-CI CH 180
19 H .~ Cl 2 -Cl 4 -Cl CH 219
CH=Ch~
H -CH2-C~ 2 -Cl 4 -CI CH 144
21 H n-C7HlS 2-CI 4-CI CH 105
22 H ~ \\ 2 -CI 4 -CI CH 151 o
23 H ~ F 2 - CI 4 -CI C11 1 73:
~ 900-9373
E x . Rl 2 R3 R4 - X ~
~ _ __ __
24 H ~ N 2-CI 4-CI CH 228-233
H ~ Cl 2 -Cl 4 -Cl N 237 - 240
.=.
26 H -C (CH3) 2- // \\. - Cl 2 -Cl 4 -Cl CH 162 -165
27 H ~ 2-CI 4-CI CH 162 -167
.,~ ,.
28 H ~ . _ J 2 -CI 4 -CI CH 228-235
'--!
29 H _ .// ;\._ Br 2-CI 4-Cl N 241-244
\.--!
H ~ ;\ 2 -CI 4-CI N 265-268
' .//~ Br
31 H \ - / 2-CI 4-CI CH 199-206
32 H _ !/ \`. - Cl 2 -Cl 4 -C l N 205 - 209
~'- Cl
. _!/ \~._ .// \\. _ Cl
33 H \. - ! \. - .! 2-Cl 4-Cl N 250-252
34 H ¦ /i ;/_N~ / CH2 ~ _ / 2-CI 4-CI CH 90_95
_ _ ~H3
H ~ -N N~ ,N 2-CI 4-CI CH 110-112
.~ - ll CH~
36 H i il i 2-CI 4-CI CH 146-160
.,~
37 H /; ;\._./; ;\,._Cl H H CH 207-214
\ = .~ '.=!
38 H _ ,, _ H 4-CI CH 216-Z19
39 H 0 ~ _ Cl H 4-CI N 181-186
. ~
-12- 900-9373
Ex. Rl 2 R3 R4 X m.p.
_ _ _ __
H ~ Cl 2-CI 4-CI CH 120-126
41 H !/ \`. N p~, ! I , ' 2-CI 4-Cl CH 115-125
42 H _!/ \\.- Cl 2-CI 6-CI CH 85-87
43 H ~ / \;. 2-CI 6-CI CH 90 93
44 H _ .// ~/._ !i ;'._ Cl 2-CI 6-CI CH 195-196
H /; \\ ~ ~_!, "`- 2-~l 4-CI CH 223-226
46 H C-C ~ ~ 4-Cl CH 240-245
N M R - Spectra
Ex. Spectra
1 6.8-7.5 (m, 6H); 6.4 (dbr, NH); 5.56 (qual J = 6.5 Hz, lH); 4.4 (d7
J = 6.5 Hz,2H);l.la(s,9H).
6 7.1-7.8(m,5H);7.0(s,lH);6.84's,lH);5.75(qua,J = 6.5 Hz,lH);
4.48(d,J - 6.5 Hz,2H).
7 6.9-7.7(m,6H);5.5'dd,J = 9 u. 6 Hz,lH);4.9(dd,J = 9 u.14 Hz,
lH);4.4(dd,J = 14 u.6 Hz,lH);2.75(s,3H);2.02(s,~H).
The required starting materials may be obtained as follows:
~'i
-13- 900-9373
A) 1-(2~4-Dichlorophe-nyl-)-2-(lH-imid-azol-l-yl)eth~lamine (for examples
1,2,6,8, 17 to 24, 26 to 28, 31, 34 to 36, 40, 41 and 45)
17.6 9 of 1-(2,4-dichlorophenyl)-2-(lH-imidazol-l~yl)chloroethane are
stirred for 2 hours at 90 with 3.8 g of lithiumazide in dimethyl~ormamide.
Water is then added, the solvent largely removed under vacuum, the residue
partitioned between water and methylene chloride and the organic phase
washed, dried and concentrated under vacuum.
The crude 1-(2,4-dichlorophenyl)-2-(lH-imidazol-l-yl)azidoethane
(Rf value in TLC identical with starting material, albeit with strong
IR band at 2100 cm 1) is hydrogenated in a hydrogenation apparatus uncler
normal pressure with 1 9 of Pd/C (10%) and glacial acetic acid as solvent.
The solvent is then largely removed and ~he residue diluted with water.
The acid aqueous phase is shaken with methylene chloride made alkaline
with caustic soda solution and again extracted with methylene chloride.
This organic phase is washed, dried, concentrated and after conversion
to the dihydrochloride the title product obtained as crystals (ethanol/
ether m.p. 227-240).
NMR: 7.2-7.55 (m, 4H); 7.0B (t, J=lHz, lH); 6.94 (t, J=lHz, lH); 4.72
(dd, J=8 + 4Hz, lH), 4.08 (AB- part of an ABX-System, JAB= 14 Hz,
AX = 4 Hz, JBX ~ 8 Hz, 2H); 1.2-1-9 (br, NH2)-
B) 1-(2,4-dichlorophenyl)-2-(lH-1,2?4-triazol-1-yl)ethylarn~ne
(for Examples 3,5~ 25,29, 30, 32 and 33)
Analogous to A)9 m.p. 107-110.
C) N-Methyl-1-(2,4-dichlorophenyl~2-(lH-imidazol-l-yl)ethylamine
(for Examples 7 and 16).
a) 2,4-Dichloro-a-(lH-imidazol-l-yl)-N-rnethylacetophenonimine
18 9 of a-(lH-Imidazol l-yl)-2,4-dichloroacetophenone and 30 ml of a
30~ alcoholic methylamine solution are heated together for 16 hours at
90 in an autoclave. The result is concentrated and the crude Schiff's
base directly further reacted.
-14- 900-9373
b) N-Methyl-1-(2,4-dichlorophenyl)-2-(lH-imidazol-l-yl)ethylamine
18.9 9 of crude 2,4-dichloro-~-(lH-imidazol-l-yl)-N-methylacetophenon-
imine are dissolved in methanol mixed with a drop of alcoholic methyl-
orange solution and alcoholic hydrochloric acid added until the colour
changes. Following addition of 4.44 9 of NaCNBH3 stirring is carried out
for 1 hour at room temperature and pH 3-4 (after two further additions of
alcoholic hydrochloric acid). The mixture is then concentrated under
rotation, the residue partitioned between methylene chloride and aqueous
NaHC03 and the organic phase dried and concentrated. The residue is
10 chromatographed over silica gel (methylene chloride/ethanol - 9/1
to obtain the title compound as an oil.
NMR: 7.44 (m, 2H); 7.33 (m, 2H); 7.08 (m, lH); 6.9 (m, lH); 3.8-4.5
(ABM-System, JAB = 14 Hz~ JAM = 4 Hz~ JBM ' ~;
1.6-2.1 (br, NH).
15 D) N-Methyl-1-(2,4-dichlorophenyl)-2-(lH-1,2,4-triazol-1-yl)ethylamine
(for Example 4)
Analogous to C), m.p. 71-72.
NMR: 7.96 (s, 2H)); 7.2-7.5 (m, 3H); 4.1-4.6 (m, 3H); 2.26 (3, 3H);
2.C (br, NH).
20 E) 4-(4-Chlorophe~)benzoic acid pyrldyl-2-thiolester (for Example 2)
-
A mixture of 4-(4-chlorophenyl)benzoic acid, 10.4 9 of triphenylphos-
phine and 8.8 9 of 2,2'-dithiodipyridine in 80 ml of methylene chloride is
stirred for 2 hours at room temperature. The solvent is then removed in
vacuum, the residue dissolved in a little ethanol and mixed with ether
25 until cloudy. Shortly thereafter crystallisation begins. The title
compound is obtained following sucking-off and drying as colourless
crystals, m.p. 153-160.
~ i
3~ 3
-15- 900-9373
F) 1-(4-Carbox~phenyl)-4-dimethylcarbamoylpiperazine (for Example 35)
a) 1-(4-Ethoxycarbonylphen~l)-fl-dimethylcarbamo~lpiperazine
2.04 9 of dimethylcarbamoylchloride are ~dded dropwise to a solution of 4.4 9
of 1-(4-ethoxycarbonylphenyl)piperazine in chlorofarm warmed to 50 and the
resulting mixture refluxed for 2 hours. The solution is removed under
vacuum, the residue mixed with 60 ml of aq. 30% NaOH and the resulting
solution stirred for 1/2 an hour at room temperature with 200 ml of
toluene. The organic phase is separated, washed, dried and evaporated.
The residue is purified by silica gel filtration (methylene chloride/
10 ethanol = 9/1) and the title compound obtained as colourless crystals,
m.p. 79-83.
b) 1-(4-Carboxyphenyl)-4-dimethy!carbamoylpiperazine
2.4 9 of 1-(4-ethoxycarbonylphenyl)-4-dimethylcarbamoylpiperazine are
refluxed for 3 hours in a mixture of 70 ml of ethanol, 8 ml of water and
15 0.8 9 of NaOH. The reaction mixture is then acidified, shaken with methy-
lene chloride, the organic phase dried and evaporated and the crude title
compound thus obtained directly further reacted.
- G) 4 Benzyl-1-(4-carboxyphen~l)piperazine (for Ex. 34)
a) 4-Benzyl-1-(4-ethox~carbon~lphenyl)piperazine
5 g of 1-(4-Ethoxycarbonylphenyl)piperazine 5.9 9 of K2C03 and 3.6 9 of
benzylbromide are heated at 100 for 1 hour in dimethylformamide. The
solvent is removed under vacuum and the residue partitioned between
methylene chloride and aqueous NaHC03.The organic phase is washed, dried
and evaporated under rotation and the crude title compound thus obtained
directly further reacted. Rf=O.9 (eluant CH2C12/C2H50H = 9tl).
b) 4-Benz~1-1-(4-carbo~e_en~ ~ iperazine
Analogous to fb) m.p. 221-229.
H) 4-Benzoyl-1-(4-carbox~phen~ ~ r Example 41)
Analogous to G).
....
% ~ 7~3
-16- 900-9273
a) 4-Benzoyl-1-(4-ethoxycarbonylphenyl)piperazine
m.p. 127-132.
b) 4-Benzoyl-1-(4-carbox~_ nyl?eiperazine
Directly further reacted.
I) 1-(2,6-Dichlorophenyl)-2-(lH-imidazol-l-yl)ethylamine (for Examples
42 to 44).
a) 2,6-Dichloro-a-bromoacetophenone
50 9 2,6-Dichloroacetophenone are dissolved in 50 ml of abs. diethylether
and then mixed with O.S g of finely powdered aluminiumchloride. To this
mixture are added dropwise over 15 minutes with thorough stirring
and ice-cooling 41.~ g of bromine. After complete addition the solvent
is removed under vacuum and the semi-solid yellow mass directly further
reacted.
NMR (CDC13) = 4.44 (2H, s, CH2Br); 7.3-7.5 (3H, m, subst.phenyl).
15 b) a-(lH-Imidazol-l-yl)-2,6-dichloroacetophenone
30 9 of crude 2,6-dichloro-~-bromoacetophenone are dissolved in 50 ml of
abs. dimethylformamide mixed with 22.9 g o~ imidazole and allowed to
react for 24 hours at room temperature. For working up the reaction
mixture is poured into about twice the quantity of sat. NaCl, extracted
20 with ethylacetate, the extract dried over sodium sulphate, the solvent
removed on a rotary evaporator and the residue chromatographed over silica
gel ~0 (dichloromethane/methanol/petroleum ether = b.p.~0-80 = 7/1/4). A
sticky, colourless oil results which is homogenous according to TLC.
NMR: 5.15 (2H, s, CH2); 7.02 (lH, t); 7.14 (lH, t) + 7.58 (lH, t);
Imidazole-ring; 7.40 (3H, s, subst. phenyl).
~27'
~3
-17- 90~-9373
c) 2-(lH-Imidazol-l-yl)-1-(2,6-dichlorophenyl)ethan- l-ol
20 9 of ~-(lH-Imidazol-l-yl)-2,6-dichloroacetophenone are dissolved in
100 ml of ethanol, mixed at room temperature and with thorough stirring
with 2.95 9 of NaBH~ and stirring continued for a further 4 hours at room
temperature. The working up proceeds by decomposition of excess hydride
with a few drops of dilute HCl, dilution with water and removal of
most of the ethanol under vacuum. The residue is shaken with dichloro-
methane and saturated NaHC03, dried over Na2S04 and evaporated. Chromato-
graphy on silica gel 60 (dichloromethane/methanol/petroleum ether = b.p.
10 60-80 = 7/1/4) yields colourless crystals m.p. 137-141.
d) 2-(lH-Imidazol-l-yl)-1-(2~6-dichlorophenyl)-1-methanesulfonylo~yethane
A solution of 12.8 9 of 2-(lH-imidazol-l-yl)-1-(2,6-dichlorophenyl)ethan-
1-ol in 50 ml abs. dichloromethane is mixed successively under ice-cooling
with 5.03 9 of triethylamine and 5.7 g of methanesulfonylchloride. After
5 hours' stirring, working up proceeds by shaking with dichloromethane and
saturated NaHC03. AFter drying over Na2S04 the organic phase is
concentrated under vacuum and the residue chromatographed over silica gel
60 (eluant as Ic)). A sticky colourless oil is obtained.
NMR: 2.70 (3H9 s, CH3SQ2); 4.42 + 4.50 (2H, dq, AB- part of an ABX-System,
JAB = 14 Hz, CH2); 5,76 (lH, dd, X-part~ JAX + JBX = 14 Hz~ -CH0-);
6,97 (lH, t, J ~ 1 Hz); 7.10 (lH, t, J = lHz) + 7.51 (lH, t, J = 1 Hz):
Imidazole-ring; 7.20-7.45 (3H, m, subst.phenyl).
e) ?-(lH~Imldazol-l~yl)-1-(2,6-dichlorophenyl)-1-azidoethane
A mixture of 12.9 9 of 2-(lH-imidazol-l-yl)-1-(296-dichlorophenyl)-l-
methanesulfonyloxyethane, 3.77 9 of sodiumazide and 2.45 9 of
lithiumchloride in 25 ml abs. dimethylformamide is thoroughly stirred
for 4 hours at 100. The result is diluted with water9 extracted with ether,
7~3
-18- 900-9373
the ether phase washed with saturated NaCl, dried over Na2S04 and
concentrated on a rotary evaporator. The resulting colourless crystals
(m.p. 45-49) are further reacted without further purification.
f) 2-(lH-Imidazol-1 yl)~ 2,6-dichlorophenyl)eth~lamine
7 9 of 2-~lH-Imidazol-l-yl)-1-(2,6-dichlorophenyl)-1-azidoethane are
dissolved in 70 ml of pyridine and mixed with so much w~ter that it just
remains clear. Hydrogen sulfide is then passed in for 30 m;nutes at 35-40.
After a further 2 hours excess hydrogen sulfide is blown off with n;trogen,
the pyridine removed under vacuum and the residue taken up in 2N HCl and
finally shaken with dich10romethane and 20% aqueous NaOH. The organic
phase is washed with saturated NaCl dried over Na2S04 and evaporated.
The colourless, sticky residue is directly further reacted.
NMR: 1.96 (2H, b, -NH2); 4,42 (2H, d, J = 7 Hz, -CH2); 5,06 (lH, t, J =
7Hz, -CH); 6,97 (lH, b), 7.04 (lH, b) -~ 7.50 (lH, b): Imidazolering;
7.10-7,40 (6H, m).
J) 1-(4-Chlorophenyl)-2-(lH-imidazol-l-yl)ethylamine (for Example 38)
Analogous to I~.
m.p. (dihydrochloride) 262-270.
K) 1-(4-Chlorophen ~ -(lH-1,2,4-triazol-1-yl)ethylamine (for Example 39)
Analogous to I.
m.p. (dihydrochloride) 214-220.
