Note: Descriptions are shown in the official language in which they were submitted.
1066709
: , . .
DESCRIPTION OF THE INVE~TION~
The imidazole carboxylates with which th~ inventlon i8
.
: 5 concèrned are generally represented by the rormuia: . ` ..
.
- . . ..
.
l OOC~
. . . H-CH3
:' '- `' ~ ` ' ' ' ' `. '
and the stereochemlcal optical ~somer~ thereor, wheretn the term : `
. .
, ~loweralXyl~ 18 selected from the group con~isting of methyl,
ethyl and propyl. The pharmaceutlcally accepta~le acld additlon
.
8alt8 thereo~ are meant to be wlthin the scope o~ ~ormula (I).
,
Compounds Or ~ormula (I) ln race~lc ~orm and methods Or
prepsrlQg same ~re descri~ed ln U.S. Pat. ~lo. 3,354,173. ~ -~
; , ' :-:
~ J . :,~ .
~ ' , ~ ,:','
~066709
The compounds of formula (I), and especially the
dextrorotatory isomers thereof, h~vin~ the R-configuration,
are very useful as short-acting hypnotic agents, and some of
them are now currently used in practice or well-known in the
art. Important members of the group of compounds within the
scope of formula (I) are, for example, (+)-methyl l-(l-phenyl-
ethyl)imidazole-5-carboxylate, generically designated as
metomidate, which is commercially available in Europe as an
injectable hypnotic for veterinary use; R-(+)-ethyl l-(l-phenyl-
ethyl)-lH-imidazole-5-carboxylate, generically designated as
etomidate, reports of which have appeared in Arzneim.-Forsch.,
21 (8), 1234 (1971), Brit. J. Anaesthesia, 45, 1097 (1973), and
Anaesthesist, 23, 150 (1974); and (+)-propyl l-(l-phenylethyl)-
lH-imidazole-5-carboxylatej generically designated as propoxate.
According to this invention, the compounds of formula
(I) are conveniently obtained by transforming l-(l-phenylethyl)-
lH-imidazole-5-carboxamide or 1-(1-phenylethyl)-lH-imidazole-5-
carbonitrile into a loweralkyl ester of formula (I), such as, -
for example, by heating,---preferably under reflux conditions,
; l-(l-phenylethyl)-lH-imidazole-5-carboxamide (II) or 1-(1-
phenylethyl)-lH-imidazole-5-carbonitrile (III) together with
an appropriate lower alkanol in the presence of a suitable acid,
preferably a strong mineral acid, such as, for example, hydro- -
chloric or sulfuric acid. The thus-obtained compounds of
formula (I) may be isolated from the reaction mixture and
further purified by ~lassical means and, if desired, trans-
formed into a pharmaceutically acceptable acid addition salt
thereof by reacting them with an appropriate acid.
~- , .- .. ..
.
- :.
- , , , . ,: :. ... . ..
~J~ 1 ,O
1~66709
.
. , N
. . ~H CH3 .
(lII) ~ . .
Since the stereochemlcal configuratlon at the asymmetric
carbo~ atom in either (II) or (III) is not altered during the
course Or the reaction, the foregoing procedure may be employed
to prepare the racemic form of the compounds (I) a~ well as the
optically pure isomeric ~orms thereof having elther the R-(+)
or S~ configuration, provided that the correspondine form
of the precursors (II) or (III) is u6ed as a starting materlal.
.
, ,
~ ~ The l-(l-phenylethyl)-lH-imidaæole-5-carboxamide (II) i
._
~and the l-(l-phenylethyl)-lH-imidazole-5-carbonltrile ~
0 used herein a6 starting material~i may ~e prepared by the fol-
` lowing sequence of reactions.
, ~ - . ~ - . . .
N~ phenylethyl)-aminoacetonitrile (IV) i8 N-acylated~
.. in the conve~tlonal manner with a lower aliphatic acylating
agent, for examplè, with . formic acid or with an approprlate
. 15 lower alkanoic acid anhydride or halide, preferably the chloride,
3 such as, for example, acetlc anhydride, acetyl chlorlde, propionic
JI' anhydr~de, and the like, to produce the correspondlng N-acyl-
aminoacetonitrile (V). The N-acylated aminoacetonitri-le i8
then C-formyl~tedusing a lower alkyl ester of formic acid, e.g.
meth~l formate, with an alkall alkoxlde, e.g. sodium methoxide,
ln an lnert solvent ~uch a~, ~or example, an aromatic hydrocarbon,
066709
JAB-150
,
e.g., benzene, toluene, xylene and the like, an ether, e.g.
tetrahydrofuran, dioxane and the like, and other aprotic
organic solvents.
The resulting alkali metal enolate salt (VI) can be
isolated by adding several volumes of ether and filtering
orf the solid salt. Alternatively the alkali metal enolate
salt need not be isolated but may be extracted with water
and the aqueous solutlon as such employed thereafter.
~ The free N-acyl-C-formylaminoacetonitrile enol (VII)
! 10 can be obtained by acidifying a~ aqueous solution of the
!
corresponding salt (VI~. Isolation of the ~ree enol ~VII)
may be effected with a water-lmmiscible solvent such as
~' chloroform. I ,
: :
. .
,~ The enol (VII) is ,then sub~ected to a condensatlon
~` 15 reaction with hydrogen thiocyanate in an aqueous solutlon- ~-
using approximately equivalent molecular quantltie6 of the
reactants to obtain 2-mercapto-1-(1-phenylethyl)-lH-im1dazo1e-
'~ 5-carboxamide (VIII). Alternatively, condensation may be
~l ~ccomplished with wàter-soluble metal salts, pre~erabiy the
. 1 ,. . . . ......................................... .. . -
alkili metal salts such as sodium and potas6ium salts of one
i~ or both of the reactant~, in which ca~e the reaction ~8 carried
I out in the pre,3ence of a strong, non-oxidizing mineral aoid, such
, as hydrochloric acid, hydrobromic acidj phosphoric acid and
the like to produce t~e ~cid form of the reacti~nts.
1 . ... .....
, , :. . .
~ 4 ~
~,' , ; , ' '
, . . . . . .. ...... .. ... .. . .... . . . .
~ - JAB-150
~06~709.
... . . . . .. .
The condensation solvent is preferably an aqueous
solvent, such as, water or aqueous alcohol, containing suf-
ficient water to retain in solution any inorganic salt which
may be formed during the course of the reaction. Although room
temperatures (20-25C ) are operable, slightly elevated tempera-
tures of a~out 40-100C. will enhance the rate of the reaction.
It is to be noted that during the foregoing condensation reaction,
which occurs in acidic medium, thè nitrile group of (VII) is
hydrolyzed to a carboxamide group.
.
The~desired l-(l-phenylethyl)-lH-imidazole-5-carboxamide
of formula (II) is then ~btained by treating the amide of
formula (VIII) with Raney-Nickel. The reaction is preferably
` carried out in a lower alkanol, e.g. ethanol, to which there `
.
i8 added an appropr~ate base, such as, for example, ammonia,
to 801ubilize the reactant (VIII).
, . . . . .
-
The l~ phenylethyl)-lH-imidazole-5-carbonitrile of
~ormula (III) is conveniently prepared by dehydratation of
j . .
the amide (II), e.g. with an amide-to-nitrile deh~drating
.,~ . .
. agent such as, for exa~ple, phosphoryl chloride, phosphorus
pentoxide, thionyl chloride and the like ~in an appropriate
s 801vent, such as, for example, pyrldine.
. ~ , . .
i'' . ~ .
~ '
i~ .
i' '
~ , . ~ . . ~ . . . . .. .
.. . . . , . ~ , ,
JAB-150
1066709
The foregoing reactions may be illustrated by the
following schematlc represe~.tation, where~n Rl stands for
hydrogen or loweralkyl.
~ CH-NH-CHz-CN = ~ ~b CH2-CN
(I~) (V)
.. . ... ~
1 . . .
O~;~R
~CH-~-C-CN
1H J~HONa
3 \ H
- (YI) . ~ ~ ~
.. -: 1 ~CH-~-C-CN
.- HCl , .CH3 ~HOH --
.. . .. , / , ' .
. ~ ~ N ~CN ( YII)
. H2N- ~
.~ . . ~ . . -. '
~i (VI~) ~
:! . ! ` _ .
Ra-Ni
. EtOH/NI~3
. PO~l
3 b (III)
pyridinc
.. .. . . . . . .. ... . .... .. .... .. ..
, ~ . , .
., . - 5a -
, ' -
,1 . , ,
, ~ ,
: .
. . . . . . . ..
JAJ3-l~jO
~066709
; It is to be noted that when the precursor (rV), used as
a starting material, is in the racemic form, then the resultin~
amide (II) and nitrile (III) are also in the racemic form.
When (IV) has either the R- or S-configuration, substantially
free of the other, the corresponding forms of (II) and (III)
will respectively be obtained. The precursor o~ formula (I~)
in racemic form as well as the optically pure isomers thereof
are described in J. Org. Chem.,~~ (21), 3286-3289 (1972).
. The amide of formula (II) and the nitrile of formula (III),
ln racemic form and in the form of their optical iæomers each
substantially free of the other, are deemed to be novel, and,
_.,
as uQeful precursors in the preparation o~ compounds of formula
(I), they constitute an addltional feature of this inventlon.
By the present inventlon there is also provided a method -
1~ of preparing substantialIy pure optical antipodes of formula~
(I) essentially free of the other starting from racemic pre-
cursors. It i8 a highly deæirable ob~ective to have such a
method available since it makes the production of optically
pure end products to a lesser degree dependent on the avail-
ability of optically pure precursors.
~ ' ` ' ' ' .
A convenient method of preparing substantially pure R- and
S-rorms Or formula (I) çompounds according to the present in- -
~, vention comprises resolving racemic l-(l-phenylethyl)-lH-Lmidazoie-
. 5-carboxylic acid into its optically active enantiomorphs and
thereafter converting each optical isomer of the acid into t~e
.
~: desired loweralkyl ester according to known esterification
~rocedures .
- - ` - 6 -
I I ' ', " ''- ~ ' ' ', ,,. ' `' , ' ' ,'; . , .` , '
.. ;~ -
1066709
The resolution of racemic l-(l-phenylethyl)-lH-imidazole-5-
carboxylic acid into its optical isomers may be carried out by salt forma-
tion with the appropriate isomeric form of a suitable optically active base,
mechanically separating the insoluble diastereomeric salt thus formed, for
example, by treatment of the acid-base salt with suitable acid, e.g., a strong
non-oxidizing mineral acid, in an amount sufficient to neutralize the basic
moiety. If the imidazolecarboxylic acid is to be isolated it is appropriate
to liberate first the free optically active base from the diastereomeric salt
by the addition of aqueous alkali to about pH ll,`thereafter extracting said
base with an appropriate water-immiscible organic solvent such as, for
example, 2,2'-oxybispropane, and ad~usting the pH of remaining alkaline
aqueous phase to neutral or slightly acidic such as, for example, acetic acid,
propionic acid and the like, whereupon the desired imidazolecarboxylic acid
precipitates. The optically active base used in the resolution is thereby
recovered and, consequently, the need for additional optically pure reagents
is minimalized.
Thus, in accordance with the present teachings, a process is provided
of preparing an optically active loweralkyl l-(phenylethyl)-lH-imidazole-S-
carboxylate which comprises resolving (-)-l-(l-phenylethyl)-lH-imidazole-5-
carboxylic acid by mixing said acid with an appropriate isomer, substantially
free of the isomer of opposite sign, of a base selected from the group consist- -
ing of l-phenylethylamine, l-naphthyl)ethylamine and 1-(2-naphthyl)ethylamine
in an inert organic solvent, mechanically separating the insoluble optically
' active l-(l-phenylethyl)-lH-imidazole-5-carboxylic acld optically active base
salt, in which the base is the same sign as the acid, treating said -acid
-base salt with a strong nonoxidizing mineral acid and esterifying the thus-
obtained optically active l-(l-phenylethyl)-lH-imidazole-5-carboxylic acid
with a loweralkyl esterifying agent directly, or first preparing the acid
chloride before esterifying to yield optically active loweralkyl l-(l-phenyl- ~- -
ethyl)-lH-imidazole-5-carboxylate substantially free of the isomer of opposite
sign.
~, -7
,~ ~
:~ , ., . . , ;, . ,. ~ : .. . .
~066709
The formation of the aforementioned diastereomeric salts in con-
ducted in an appropriate inert organic solvent such as, for example, a lower
alkanol, e.g. ethanol, propanol, 2-propanol, and the like, preferably under
reflux conditions, Suitable optically active bases for the purposes.of this
invention, include, for example, the dextro- and levo-forms of l-phenylethy-
lamine, l-(l-naphthyl)ethylamine, and l-(2-naphthyl)ethylamine, the first
being preferred.
For examplè, when R-(~)-l-phenylethylamine is added to a solution
of racemic l-(l-phenylethyl)-lH-imidazole-5-carboxylic acid in an appropriate
solvent, an addition salt of R-(+)-l-(l-phenylethyl)-lH-imidazole-5-carboxylic
acid with R-(+)-l-phenylethylamine in substantially pure form is precipitated,
from which the free acid may be obtained in essentially optically pure form.
:
-7a- : :
~"' ..
" : .
1066709
- The thus-obtained R-(+)-l-~l-phenylethyl)-lH-imidazole-
5-carboxylic acid or the addition salt thereof with R-(+)-l-
phenylethylamine is easily converted into a R-(+)-loweralkyl 1-
(l-phenylethyl)-lH-imidazole-5-carboxylate, designated as R-(+)
(I), according to conventional esterification methods, for
example, by refluxing the acid or the addition salt in an ap-
propriate lower alkanol in the presence of an appropriate strong
non-oxidizing mineral acid such as, for example, hydrochloric or
sulfuric acid. Alternatively, the R-(+) acid may be transformed
into an acyl halide according to standard procedures and the
acyl halide reacted with an appropriate lower alkanol to obtain
the desired ester. For example, the hydroxy function of the
acid can be readily transformed into a chloro function by re-
action of the acid with such chloro-transfer agents as oxalyl
chloride, sulfinyl chloride (thionyl chloride) which is prefer-
red, sulfuryl chloride, phosphorus oxychloride, phosphorus tri-
chloride and phosphorus pentachloride. The thus-obtained R-
(+) (I) product may be further purified by known purification
procedures and, if desired, transformed into a pharmaceutically - ~
acceptable acid addition salt thereof by reacting it with an - ~ -
appropriate acid.
The same procedure may be utilized equally well,
mutatis mutandis, to separate S-(-) l-(l-phenylethyl)-lH-
imidazole-5-carboxylic acid, using, however, the alternate S-
(-) isomeric form of the optically active base. Similarly,
esterification of the thus-obtained S-(-) acid yields the S-(-)
form of the formula (I) esters, designated as S-(-) (I).
Whether the R-(+) or S-(-) form of the carboxylic ~ ;
acid is removed from the medium in diastereomeric salt form, ;--
the respective enan~iomer which remains in the solution may be
recovered by conventional means, for example, by evaporation of
the mother liquor from which the precipitated diastereomer was
1066709
obtained or by dilution with an appropriate non-solubilizing
solvent, and, if desired, transformed into a lower alkyl ester
of formula (I), having the corresponding configuration.
The racemic l-(l-phenylethyl)-lH-imidazole-5-carboxy-
lic acid used as a starting material herein is described in
U.S. Pat. 3,354,173 and may be prepared according to the pro-
cedures outlined therein.
It is believed that the substantially pure optically
isomeric forms of l-(l-phenylethyl)-lH-imidazole-5-carboxylic
acid and addition salts thereof with optically active bases,
essentially free of their other respective enantiomers, are
novel and, as useful intermediates herein, they constitute an
additional feature of this invention. In addition to salt
formation with bases, the dextro- and levo-forms of the imida-
zolecarboxylic acids may also form acid addition salts with
acids.
In view of the basic properties of the imidazole
ring, it is obvious that substantially pure optical isomers of
the desired imidazole-5-carboxylic acid esters of formula (I)
may alternatively be obtained by resolving a racemic mixture of
said esters with an appropriate strong optically active acid such ~
as, for example, the dextro- and levo-forms of 10-camphorsul- -;
phonic acid r 3-bromo-camphor-9-sulphonic acid and the like, by
the application of methodologies known to those skilled in the
art. ~ -
Since one of the optically isomeric forms, more par-
ticularly the one having the S-(-) configuration, of the com-
pounds of formula (I) is less perferred as a hypnotic agent, it
would be economically advantageous is such S-(-) form of the
compounds (I) as well as of the precursor carboxylic acid could
be further utilized in the production of the desired dextro-
rotatory isomers R-(+) (I), for example, by first racemizing
_g_
.
, .. .. . . , "., . ' . , .
.. .. . .. .. .. . .
1066709
such S-(-) forms and then resolving the thus-obtained racemate
as previously described. Such an objective is also fulfilled
by the present invention.
It has thus been found that S-(-) l-(l-phenylethyl)-
lH-imidazole-5-carboxylic acid as well as S-(-)-loweralkyl 1-
(l-phenylethyl)-lH-imidazole-5-carboxylate may be transformed
into their respective racemic forms upon treatment with a
catalytic amount of an appropriate strong base, preferably in
an appropriate solvent. Suitable bases for this purpose in-
clude strong alkali metal bases, such as, for example, alkali
metal hydrides, e.g., sodium hydride, and the like; alkali
metal loweralkoxides, e.g. potassium t-butoxide, sodium
methanolate, sodium ethanolate and the like; alkali metal
amides, e.g., sodium amide and the like; and certain organo- -
metallic compounds such as, for example, butyl lithium and
phenyl lithium. When the compound subjected to racemization
is S-(-) l-(l-phenylethyl)-lH-imidazole-5-carboxylic acid, it
is preferably used in the form of a metal salt, in which case
less of the basic catalyst is to be employed.
Suitable solvents for the racemization include polar -
organic solvents such as, for example, hexamethylphosphoric ~ -
triamide, dimethyl formamide and dimethylsulfoxide. Somewhat
elevated temperatures are appropriate to enhance the rate of
racemization and preferably the reaction is carried out in an -~
inert atmosphere at temperatures of from about 20C to about
120C. The reaction mixture is allowed to cool, then diluted
with water, and the resultant aqueous phase is separated and ~ -
acidified to about neutral pH to yield the racemic acid in
crystalline form.
When the compound subjected to racemization is an .
isomer of l-(l-phenylethyl)-lH-imidazole-5-carboxylic acid, the
resultant racemate may be obtained from the reaction mixture by
-r -10-
~ 066709
extraction with water. Acidification of the aqueous extract
to about neutral pH yields the racemate in crystalline form.
The racemic form which is obtained may in turn be resolved in-
to its dextro- and levo-isomeric forms according to the pro-
cedure described herebefore.
' ''
:- .
j, ~
,. .
, ~ .
-lOa-
. ~ .
,:~ - : . : :,
. ~ , . .
. . .
1066709 JA~
.
~ When an isomeric form of a loweralkyl ester of
¦ formula (I) is racemized, the resultant racemate may be
j obtained from the reaction mixture by extraction with an
inert organic non-polar solvent, for example, an aromatic
hydrocarbon such as benzene, toluene, xylene and the like.
The racemic ester which i8 obtained may be hydrolyzed to
obtain the corresponding free acid which may subsequently
be sub~ected to resolutlon.
Although emphasis is laid on the racemizatlon of the less
desired le~o-isomers, the sama procedure is applicable to the
; dextro-isomers when it is desirable to transform a dextro- -
lsomer into a racemic mixture. Such a procedure i8 al80
; ~ intended to be within the scope of this invention.
.
_ The ~ollowing examples are given in order to illustrate
l~ and not to limlt the invention thereto. Unless otherwise
, state* all parts are by weight and the symbol [a] stands ~
-` ~or ~ . I ~ _
' . ' ,
:
' ' ' `
.' . ' ',
. . ~
'' ,- ' '
,` ; , ' - 11- . .
~ , r
.. . . .
1066709
EXAMPLE 1
To a stirred mixture of 104.1 parts of (+)-2-rN-
(l-~henylethyl)amino]acetonitrile and 1440 parts of dimethyl-
benzene are added dropwise 66 parts of formic acid (slightly
exothermic reaction). Upon completion, stirring is continued
for 3 hours at reflux temperature (water-separator). The
reaction mixture is cooled to about 60C and washed succes-
sively with water, a sodium bicarbonate solution, a diluted
sodium hydroxide solution and agàin twice with water. The
organic phase is separated, dried, filtered and evaporated.
The residue is crystallized from 2,2'-oxybispropane. The
product is filtered off, washed with 2,2'-oxybispropane and
dried, yielding (+)-N-(cyanomethyl)-N-(l-phenylethyl)-
formamide (41%); m.p. 78.9C.; [~]= +60.90 (1% CH30H).
To 200 parts of ethanol are added portionwise 12.5
parts of sodium. When all sodium is entered into solution,
the ethanol is distilled off while meantime 900 parts of di-
methylbenzene are added dropwise. Upon completion, the whole
is allowed to cool to room temperature. Then there is added
dropwise, at a temperature of about 15C., a solution of 50
parts of (+)-N-(cyanomethyl)-N-(l-phenylethyl)formamide in 80
parts of ethyl formate, followed by the addition of 90 parts of -
dimethylbenzene. The mixture is stirred overnight (about 16
hours~ at room temperature. 300 Parts of water are added and
the whole is further stirred for 15 minutes. The layers are
separated and the organic phase is extracted with water. 300 -
Parts of trichloromethane are added to the combined aqueous
phases. The whole is heated to 50C. and acidified with a
hydrochloric acid solution. The layers are separated and the ;~
-
-12-
, ' ! . , ' . . ~ : , . , , , , :, . ' ' -
," ' . .. ~ .. . ' ,,
~066709
aqueous phase is extracted with trichloromethane. The com-
bined organic phases are dried, filtered and evaporated,
yielding (+)-N-(l-cyano-2-oxoethyl)-N-(l-phenylethyl)-
formamide as a residue. -
To a stirred mixture of 66 parts of (+)-N-(l-cyano-
2-oxoethyl)-N-(l-phenylethyl)formamide, 36 parts of hydro-
chloric acid solution, 200 parts of water and 160 parts of
ethanol is added dropwise a solution of 2g parts of potassium
thiocyanate in 50 parts of water. Upon completion, stirring -
is continued for 3 hours at reflux temperature. While cooling
to room temperature, the product is allowed to crystallize.
It is filtered off, washed with a mixture of ethanol and
water (1 : 1 by volume) and recrystallized from ethanol, ;
yielding, after drying in air, (+)-2-mercapto-1-(1-phenyl- -~
ethyl)-lH-imidazole-5-carboxamide hydrate; m.p. 245~3C.;
[a] = +84.7,(c = 1% CH30H).
To 80 parts of ethanol, previously saturated with
gaseous ammonia, are added 2.3 parts of (+)-2-mercapto-1-(1-
phenylethyl)-lH-imidazole-5-carboxamide hydrate and 6 parts
of Raney-nickel. The mixture is stirred and refluxed for 2
hours and thereafter allowed to cool to room temperature.
The Raney-nickel is filtered off and the filter-cake is washed
with ethanol. The filtrate
I066709
~ ~ ,................. . . . .
;8. evaporated in ~racuo and the residue is puri~icd by column-
' chromatography over silica gcl using a mixture of trichloromethane
and 5% of methanol as eluent. The pure fractions are collected
and the eluent is evaporated, yielding t+)-l-(l-phenyl-
ethyl)-lH-imidazole-5-carboxamide, essentially free Or
! lts (-)-isomer, as a residue.
To a stirred and cooled (-1 0C. ) solution of 3. 7 parts of
phenyleth~,rl)-lH-imidazole-5-carboxamide in 50 parts of
pyridine ~re added dropwise, during a 15 minute period, 3. 4past~
of phosphoryl chloride. The mixture is allowed to rcach room
temperature; then heated in a boiling water-bath-~or 1.5 hrs.
The reaction mixture is cooled to room temperature and poured
- `onto 250 parts of ice-water. The precipitated product i8 fil-
tered o~f, washed with water and dissolved in trichloromethane.
The solution is drled, filtered and evaporated. The golid
residue i8 crystallized ~rom a mixture of 2,?'-ox~bispr~pane
and ethanol, yieiding ~+)-i-(l-phenylethyl)-lH-im1dazole-
5-carbonLtrile, m.p. 129.3C; [~] - ~40.56 (c - 1~% CH3pH).
.. _ ...... ...... . . .. . -
~, . ,
-- .
: , ' `.~ ' ~' " ' '' -
', . '
. ~ . - .
,
. ~ . , .. ~ .. . ... .. . .
-- 14 -
1066709
EXAMPLE II
A. To a stirred mixture of 110 parts of (-)-2-[ N-(l-
phenylethyl)amino]acetonitrile and 1500 parts of dimethyl-
benzene are added dropwise 70 parts of formic acid (slightly
exothermic reaction). Upon completion, stirring is continued
first for 3 hours at reflux temperature (water-separator)
and further over week-end (about 63 hours) at room temperature.
The reaction mixture is heated to 60C and washed successively
with water, a sodium bicarbonate solution, a diluted sodium
hydroxide solution and again twice with water. The organic
phase is separated, dried, filtered and evaporated. The
residue is crystallized from a mixture of 80 parts of ethanol
and 108 parts of 2,2'-oxybispropane. The product is filtered
off and dried, yielding 46.5% of (-)-N-(cyanomethyl)-N-(l-
phenylethyl)formamide; m.p. 78.8C.; [c~] = -60.7 (c = 1%
CH30H).
To 200 parts of ethanol are added portionwise 16
parts of sodium. When all sodium is entered into solution,
the ethanol is distilled off while meantime 1080 parts of
dimethylbenzene are added dropwise. Upon completion, the
whole is allowed to cool to ~oom temperature. Then there is
added dropwise, at a temperature of about 15C., a solution --
of 60 parts of (-)-N-(cyanomethyl)-N-(l-phenylethyl)formamide
in 96 parts of ethyl formate, followed by the addition of 90 :
i.., . ::: ~
parts of dimethylbenzene. The mixture is stirred overnight at
room temperature. 300 Parts of water are added and the whole
is further stirred for 15 minutes. The layers are separated
and the organic phase is extracted with water. 300 Parts of
trichloromethane are added to the combined aqueous phases.
--15--
- . ,: . . ,
- . , ,
Jo~ o
1066709
~ ,............. ......................................................
The whole is heated to 50C. and acidified ~vith a hydrochloric acid
: solution. The layers are separated and the aqueous phase is
` extracted with trichloromethane. The combined organic phases
are dried, filtered and evaporatcd, yielding (-)-N-(l-cyano-
2-oxoethyl)-N-(l-ph~enylethyl)formarnide as a residue.
,1 . ~, ' .......................... .
Il . . . .
. ~ , , ,` ' .
.
To a stirred mixture of 66 parts of (- ~-N-(l-cyano-2-oxo-
ethyl)-N~ phenylethyl)formamide, 36 parts of hydrochloric acid
solution~ 200 parts of ~vater and 160 parts of ethanol is added
dropwise a solution of 29 parts of potassium thiocyanate in 50 pzrts
~of water. Upon completion, stirring is continued for 3 hours at
renux temperature. While cooling to room temperature, the product
iB allowed to crystallize. It is filtered off, washed with a mixture
o ethanol and wator (1: 1 by volume) and recrystallized from ethanol,
yielding, after drying at the air, ( - )-2-mercapto- 1- ~2-phenylethyl) -
I H-imidazole - 5- carboxamide hydrate; m. p. 244. 8 D C.;
~7 = -85~ 8 (c = `1% CH30H).
`I . , . "
.
. - . _,
! To 80 parts of eth;anol, previously saturated with gaseous
- ammonia, are added 2 . 3 parts of ( - ) - 2-me rcapto- 1- (2 -phenylethyl) -
lH-imidazole-S-carboxamide hydrate and 6 parts :of Raney-nickel.
~) The mixture is stirred and~re~luxed for 2 hours and
thereafter allowed to cool to room temperature. Thc Raney-nickel is
filtered off and the filtcr-cakc is washed with ethanol. The filtrate
.. ~ ' . .r
.
, '
1066709
is evaporated in vacuo and the residue is purified by column- -
chromatography over silica gel using a mixture of trichloro-
methane and 5% of methanol as eluent. The pure fractions
are collected and the eluent is evaporated, yielding (-)-1-(1-
phenylethyl)-lH-imidazole-5-carboxamide, essentially free of
its (~)-isomer, as a residue.
B. To a stirred and cooled (-10 C.) solution of 3.7
parts of (-)-l-(l-phenylethyl)-lH-imidazole-5-carboxamide in
50 parts of pyridine are added dropwise, during a 15 minute
period, 3.4 parts of phosphoryl chloride. The mixture is
allowed to reach room temperature then heated in a boiling
water-bath for 1.5 hrs. The reaction mixture is cooled to
room temperature and poured onto 250 parts of ice-water. The
precipitated product is filtered off, washed with water and
dissolved, in trichloromethane. The solution is dried,
filtered and evaporated. The solid residue is crystallized
from a mixture of 2,2'-oxybispropane and ethanol, yielding
(-)-l-(l-phenylethyl)-lH-imidazole-5-carbonitrile; m.p. 128.7C.; -
[a] = -40.23 (c = 1% CH30H).
By repeating the procedure of Example II-A and using
an equivalent amount of (+)-2-~N-(l-phenylethyl)amino]aceto-
nitrile as a starting material there is obtained (+)-1~
phenylethyl)-lH-imidazole-5-carboxamide; m.p. 136.5-137C.
By repeating the procedure of Example II-B and
using an equivalent amount of (+)-l-(l-phenylethyl)-lH-
imidazole-5-carboxamide in place of the (-)-isomer used there
in, there is obtained (+)-l-(l-phenylethyl)-lH-imidazole-5- ~ -
carbonitrile; m.p. 97-99C.
- -17-
" . . . ~ . ~ ~ - . . -
. , - . : -. - - : .
JJ~ 150
1066709
EX~ PLE III
A. To a stirred mixture of 40 parts of ethanol and
3 parts of ( + ) - l - (l - phenylethyl) - l H- imidaz ole - 5- carboxamide
there are added slowly lO parts of concentrated sulfuric acid.
Upon completion, stirring at refl~c iæ continued for 7 hours.
Ater this period, the mixture is al~owed to cool to room tem-
perature and poured onto crushèd ice. The ethanol is distilled of,
and the aqueous phase is alkalizcd with sodium hydroxide and
extracted three times with trichloromethanc. Thc combined ex~racts
are dried, filtered and e~aporated The residue is converted into
the 8ul~ate salt in 2-propanol and 2, 2'-oxybispropane. The salt
i~ filtered off, washed with 2, 2'-oxybispropane and driedj
yielding R- ( ~ )-ethyl 1- (o.-methylbcnzyl)- S-imidazolccarboxylato
suL{ate; m. p. lll C.; Ca~ D = ~22. l (c = l~0 CH30H).
~ . . . .
B. The foregoing procedure was repeate~, except that
the ~ phenylethyl)-lH-imidazole-5-carboxamite used therein
was replaced by an equivalent amount of ( - )-l -(1 ~phenylethyl)-lH- --
imidazole-S-carboxamide and there was obtainet ~- )-ethyl
p}ienylethyl) -1 H-imidazole - 5- carboxylate sulate;
[~ 22 S' (c - I % CH30H)-
- ~ '
',~ '
.
.
- 18 -
.
JAn-l~o
.
~066709
` ` EXAMPLE IV
_ _
A. Gaseous hydrogen chloridc is introduced througn
- 40 parts of ethanol till saturation while cooling at 0C. Then there
are added 2. 5 parts of (+)-l-(l-phenylethyl)-lH-imidazole-5- .
carbonitrile and the whole is stirred and refluxed for 24 hours.
The reaction mixture is poured onto water. The whole is aL`calized
with sodium hydroxide and extracted three timcs with trichloro-
mothane. The combined extracts are dried, filtered and evaporated.
Tho residue is converted ;nto the sul~ate salt in 2-propanol and
2, 2~-oxybispropane. The precipitated sulfate salt is filtcred off,
washed with 2, 2'-oxybispropane and dricd, yielding R~ ethyl
l - (a-me thylbenzyl) - 5- imidazole carboxylate s ulfate ; mp. I 1 1 . 7 C.;
Ca7 D0 = t22. 4 (c = l % CH30H).
.
.
B. The foregoing proccdure was repeated, except thzt
the ~ phenylethyl)-lH-imida~ole-5-carbonitrile used th¢~ei~
is replaced by an equivalent amount of ( - )- l - tl -phenylethyl~ - l H-
imidazole-5-carbonitrile, yielding ( )-ethyl l~ phenylethyl)-
lH-imidazole-5-carboxylate sulfate; Ca~ = -22. 3 (c = I% CH30H).
.. . . .
: . . . .
. ; . . , - ' '~ ' . , .
. " , ' , ' ' ' ~' .
:
,
.
'' ', , ~ ~
.
. .
-- 19 --
1066709
FXAMPLE y
.
To a stirred and refluxing mlxturc of 13 p~rts of
( ~ (1 -phenyle thyl) - 5- imidaz,ole carbox)~lic acid and 2 00 parts
of 2-propanol are addcd 3. 6 parts of (- )-~I-methylbenz~nc-
methanamine and the whole is stirrcd and refl~Lxed for 10 minutes.
The reaction mixturc is allowcd to cool to room tempcrature.
,~ The precipitated product is filtered off (the filtrate i8 set aside),
washed with 2-propanol and crystalli~ed from 160 parts of
2-propanol. It is îiltercd o~f and dried over wcek-end in ~acuo
at 60-C., yielding (-)~ -phenylethy~)-lH-irnidazole-5-
c~rboxylic acid salt with (-)-a~methylbenz~nemethanamine, .
m.p. 194C.; [aJD = -51.0 (c = 1~ in water).
To tho.filtrate (see above) arc addcd 3. 6 parts of (+)-~L-methyl-
benzencmethanamine and the-whole is stirred and refluxed for
10 minutes. The reaction mixture is allowed to cool to room
temperature. The precipitated product is filtered oiif, washed
wit~ 2-propanol ~nd dricd in vacuo for 4 hours at 60C., yielding
(~)-l-(l-phenylethyl)-lH-imidazole-5-carboxylic acid salt
w;th (~)-c-mcthylbenzenemcthanamine; m.p. 190~3C.;
~a 7D = ~52. 9 (c = 1 % in water).
. i , .. .
. , . . ;.. _
.. . .
'~ ' ,. ' , ~ , ' . . - - . " ,
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- ` ~ .. ...
.
-
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1 - . ... . .
.~
.,
.
. , . ' . ,`',
. - 20 -
1066709
EXAMPLE VI
A stirring mixture of 2.55 parts of (+)-a-methyl-
benzylamine salt with R-(+)-l-(~-methylbenzyl)-5-imidazole-
carboxylic acid and 24 parts of dry absolute ethanol is sat-
urated with gaseous hydrogen chloride. Upon completion,
stirring is continued for 7 hours at reflux temperature, while
gaseous hydrogen chloride is still introduced. The reaction
mixture is evaporated and the residue is taken up in 30 parts
of water. The resulting solution is adjusted to pH = 6 with
a sodium hydroxide solution 10N and the product is extracted
three times with trichloromethane. The combined extracts
are dried, filtered and evaporated. The residue is takén up
in 2.4 parts of 2-propanol and the solution is filtered. The
filtrate is acidified with sulfuric acid and warmed for a
while. 2,2'-Oxybispropane is added till almost turbid and
upon scratching, the product is precipitated while cooling in
an ice-bath. It is filtered off, washed with a mixture of 2-
propanol and 2,2'-oxybispropane, and dried, yielding 80% of
R-(+)ethyl l-(a-methylbenzyl)-5-imidazolecarboxylate sulfate;
[a] = +22.5 (c = 0.1~ H2O).
EXAMPLE VI I
A stirring mixture of 2.55 parts of S-(-)-l-(l- -~ -
phenylethyl)-lH-imidazole-5-carboxylic acid salt with (-)-
iP-,
a-methylbenzenemethanamine and 24 parts of dry absolute
ethanol is saturated with gaseous hydrogen chloride. Upon
completion, stirring is continued for 7 hours at reflux - -
temperature, while gaseous hydrogen chloride is still intro-
duced. The reaction mixture is evaporated and the residue
is taken up in 30 parts of water. The solution is adjusted
-21-
, .. : . . . .: .: .. , ~ ., . . . - -
Jh)~-] ,~i
. 1066709
.
to pH = 6 with a sodium hydroxide solutior~ lON and thc product
is extracted three times with trichloromethane. The combincd
extracts are dricd, filtered and evaporated. The residue is
converted into the nitrate salt in methylbenzene while cooling
in an ice bath, Thc salt is filtered off, washed with methylbcnzene
and dried, yielding 52% of S-(- )-ethyl l-(~-methylbcnzylj-
imidazole-5-carboxylate nitrate; ~7 = -31, 9 (c = 0. l% H2O).
1. ` .
. . ', ............... . . .
. ' . ' ` ' '
` EXAMPLE VIII
. ' ' . ', , ,
.~ ,
A. A mixture of l part of (+)-a-methylbenzylamine
........... ... salt w~th R-(+)-l-(a-methylbenzyl)-5-imidazolecarboxyl~c acid
and 6 parts of sodium hydroxidc solution lN is shaken in a closed
tube till all solid en~ers solution (pH = ~ ll). l~e resulting solution
is shaken five times for l minute, each time ater the addition of
l. 4 parts of 2, 2'-oxybispropanc. The organic phases are combined
(the a~caline aqueous phase is set aside) and evaporated, yielding
R~ a- methylbenzylamine.
The allcaline aqueous phase (see above) is adjusted to pH = 6. 2 with
acetic acid. While cooling in ice-water and upon scratching, thc
product is precipitated. It is filtered off and crystallized twice frorn
2-propanol, yielding, after drying for 3 hours in vacuo at 60C.,
R-(~ ta-methylbenzyl)-S-imid2zolecarboxylic acid; m. p. 155C,;
~7 = t65- ~- (c = 1% H20)
.
- . '
: . ,~ ' .
-
JAE~-150
1066709
B. ~y repeating thc foregoing procedure, exccpt that
an equivalent amount of (~ phenylethyl)-lH-imidazole-5-
carboxylic acid salt with (-)-a-methylbenzenemethanamine
iB u~ed, there is obtained (-)-l-(l-phenylethyl)-l~-isnidazole-5-
carboxylic àcid; m.p. 155.2C.; ~CIJD = -67.8O (C - O.1% }~2O).
.
.
EXAMPLE _IX ~ .
~ A. A mixture o~ 10 parts of R-( t) 1-(a-methylbenzyl)-
5-imidazolecarboxylic acid and 105 parts of sulfinyl chloride i8
stirred and renuxed ~or 2 hours. The reaction mixture is cooled
and diluted with 2, 2'-oxybispropane. The precipitated product is
~iltered off, washed with 2, 2'-oxybispropane and dried, yieldihg
90% of (~ phenylethyl)-lH-imidazole-5-carbonyl chloride
hydrochloridc. I ~ _
- "' ':
B. A mixture of 25. 5 pàrts of (-)-l-(l-phenylethyl?-
lH-imida~ole-~;-carboxylic acid and 280 parts of sulfinyl chloride
is ~tirred and refluxed for 2 hours. The reaction rnixture is
coolcd in an icc-bath. The product crystallizes upon the addition
of 2, 2'-oxybispropane. It is filtered off, washed with 2, 2'-oxybis-
propanc and dricd, yielding 9~% of ( - )-l-(l-pheylcthyl)-lH- ~ -
imidazole-S-carbonyl chlor1de hydrochloridc.
,: .
.
~ ,~. ~ . ,, .
. .
J~
I
1066709
. . . ` `~ .
l EXAMPLE X
: : ' ',;, , . :
. ' . '''.' '' "" '
A mixture of 5. 5 parts of (~)-1-(1-phenylethyl)-1~-
imidazole-S-carbonyl chloride hydrochloridc and 80 parts of
methanol is stirred and re1uxed overnight. The reaction mixtu~e
i i~ cooled and evaporatcd. The resi~ue is dissolved in 100 parts
of water, a~kalized with sodium hydroxide and the product is
oxtracted with 2, 2'-oxybispropane. The extract is dried, filtered
and evaporated, The residue i5 converted into the sulfate salt in
. 2-propanol and 2, 2i-oxy~ispropane. The salt is filtered of, washed
with 2, 2'^oxybispropane and dr;cd, yicld~ng 73% of (+)-methyl
¦ 10 1~ enylethyl)-lH-imidazole-5-carboxylate sulfate; m.p. 103.8-C.;
~o;7 = +20. 51~ (c = 1% CH30H).
, ... .
~1
. . , , . ' - .
.,
~, . , ,.................... .
`~ ~ EXAMPLE XI
.. . ._
, .
A mixture of 5. 5 parts of (~ (l -phenylethyl)-lH-imidazole-
S carbonyl chloride hydrochloride and 80 parts of l-propanol is stirred
; ~nd lcnuxed overnight. The reaction mixture is cooled and~evaporated.
1~ 15 The sosidùc is dissolved in 100 parts of water and the solution is
'! , ' alkalizod with a sodium hydroxide solution. The product is extracted
witll 2, 2'-oxybispropane. The extract is dried, ~iltered and
evapor2ted. Thc residue is converted into the sulfate salt in
2-propanol and 2, 2'-oxybispropane. The salt is;filterèd off, wasked
~ith 2, 2'-oxybispropane and dried, yielding 65% of ( ~)-propyl
pl enylelhyl)-lH-imidazole-5-carboxylate sulrate hydrate;
m.p. 106-C.; [Q~ - ~22. 68 (c = 1~ Cl-I301I).
. :
' ' .
.
.-- . , .
.. . .. . . . .
t
. JAJ~ 0
1066709
~ .- .................. EXAMPLE XII
~ ' ' . .,
A mixture of 5. 5 parts of (- )-l-(l-phenylethyl)-lH-
~midazole-5-carbonyl chloride hydrochloride and 80 parts of
`methanol is stirred and refluxed overnight. The reaction mixture
: i8 cooled and cvaporated, The residue is dissolved in water and
the solution is all~alized ~vith a sodiùm hydroxide solution 60%.
The product is extracted ~vith 2, 2'-oxybispropane. The extract
i6 dried, ~iltered and evaporated. The residue is converted into
. the sulfate salt in 2-propanol and 2, 2'-oxybispropane. The salt
. . i8 filtered off and dried, yielding 60% of (- )-methyl l-(l-phenyl-
ethyl)-lH-imidazole-5-car~oxylate sulfate; m.p. 97 8C,;
r~7 = -22 39 (c ~ 1% CH30H).
.'.
. ' ''
l .. ..
: . . . . ..
.~ : ~ ' - . ',' ' , ' '.''. ' ' ,
EXAMPLE XIII
- ~ A mixture of 5. 5 parts of (-)-l-(l-phenylethyl)-lH-
` imidazole - 5- carbonyl chloride hydrochloride and 8 0 parts of
` l-propanol is stirred and renuxed overnight. The reaction m~xture
~6 coolcd and evaporated The res~due is dissolved in water. The
.~ ~olution is alkalized with a sodium hydroxide soiution 60%. The
pro~uct is extracted with 2, 2'-oxybi~propane. The extract is
?~ ¦ dricd, filtered and evaporated. Thc residue i8 converted into
the ~ulfate salt in 2-propanol and 2, 2'-oxybispropane. Ihe salt
~t 1 20 i8 filtered off and dricd, yieldin~ 60% of (-)-propyl l-(l-phenyl-
-~' . ethyl)-lH-imidazole-5-carboxylate suliate hydrate; m. p. 73. 3C.;
L~ 22.24- (c- 1% C~I30H~. -
.;
,j. ~,
; i . . ' , .. .
, .
'` 7 . . _ ''
. ~, , '. ..
- J~7-i 50
~066709
EXAMPLE XIV
... . . ...
A solution of 4~. 5 part~ of ( - )- ethyl 1- (1 -phenylethyl) -
lH-imidazole-5-carboxylate sulfate in 500 parts of water i~ aL~alized
with 14 parts of a sodium hydroxide solution 50%. The product is
~xtracted twice with 325 parts of dichloromethane. The combined
S extracts are dried, filtered and evaporated in vacuo. The residue
is cry~tallized from 2, 2'-oxybispropane, yielding ( - )-ethyl
phenylethyl) -1 H-imidazole - S- carboxylate .
..
'.~. ' ' .
Amixture of 12.21 parts of (-?-ethyl l-(l-phenyIethyl)-
lH-imidazole-5-carboxylate, 1. 9 parts of a 61, 8% suspension o
10 sodium`hydride in mineral oil and 50 parts of hexamethylphosphoric
~ triamide is heated to 100C. while Argon-gas is introduced, and
further stirred at this temperature for 20 hours. The~mixture is
allowed to cool to room temperature and there are added 110 parts
of benzene. The whole i~ washed threc times with water. The
15 organic phase is dried, filter~ed and evaporated. The re~;idue is
con~rerted into the hydrochloride 6alt in 2-propanol. The crude salt
ltered off and crystallized from 2, 2'-oxybispropane, yielding
` (+)-ethyl 1~ phenylethyl)-lH-imidazole-5-carboxylate hydrochloride;
m. p. 13 9. 5 C.
.~ ~ . , .
. ~. ~ . .
'
~ .` . .. . .
~ , .
~ . . .
~26~ ;
; , : .
~,
'~' . , ' ' ""',,.. . ' ' .
,. .,: " . ~- . .. . -.
J ~ I 50
1066709
EXAMPLE XV
A mixture of 17. 7 parts of (- )-l-(l-phenylethyl)-lH-
imidazol`e-5-carboxylic acid, 3. 28 parts of sodium hydroxide and
120 part6 of 2-propanol is stirred and refluxed until the reaction,'
mixture becomes homogenous and thereafter for 1 further hour.
5 During reflux part of tho product crystallizes out. The reaction '
mixture is allowed to cool to room temperature and the precipitated
" ' product is filtered off. The product is washed with 2-propanol and
dried in vacuo, yielding (-)-l-(l-phenylethyl)-lH-imidazole-5-
carboxylic acid sodium salt.
t
.
~ .
. .
A mixture of 14. 3 parts of (-)-l-(l-phenylethyl)-lH-
;1 imidazole-5-carboxylic acid sodium salt, 1, 9 parts of a 61. 8%
suspension Qf sodium hydride in mineral oil and 60 parts of hexamethyl- -
1 phosphoric triamide i~ stirred for 20 hours at 100C, under Argon
` ' atmQsphere. The mixture i~ allowed to cool to room temperature,
15 and poured onto 150 parts of water. The whole is washed three times_
` ~ j with 200 parts of dichloromethane, The aqueou~' phase i8 neutralized
(pH 7) with acetic acid and the product i8 allowed to crystallize.,
", ~, The, product is filtered off, dried. and recrystallized from ethanol,
~, j , ' yielding (+)~ phenylethyl)-lH-imidazole-5-carboxylic acit;
,, 20 m.p.188C. ' .
:~' ' '
.' ` ` ,~.
: ,
,~
.. ..
' 1 ` ` ' !
`'~'
,,'
,~ - -27-
.. . . ..
.. . . . .
1066709
EXAMPLE XVI
40 Parts of R-(+)-ethyl l-(a-methylbenzyl)imidazole-
5-carboxylate nitrate are dissolved in water and the solution
is alkalized with sodium carbonate. After extraction with
chloroform, the latter is dried and evaporated. The residue
is dissolved in diisopropylether and the solution is acidified
with gaseous hydrogen chloride: an oil is precipitated. It
is dissolved in water, alkalized withammonium hydroxide and
the free base is extracted with chloroform. The extract is
dried and evaporated. To the residue are added a few parts of
diisopropylether and the whole is seeded with a crystal of
dl-ethyl l-(~-methylbenzyl)imidazole-5-carboxylate. After
cooling for 4 hours at -20C., the precipitated product is
filtered off and dried, yielding 20 parts of R-(+)-ethyl
l-(~-methylbenzyl)imidazole-5-carboxylate; mp. 67C.;
~20: +66 (c = 1% ethanol).
D
' ::
`''.-'.'',
~i '' . . .
,~
: ' .
. :.
!,~ ,, '
,
~ .
-28-
..
.. : ...... . : .
