CA1066709A - Preparation of loweralkyl imidazole carboxylates - Google Patents
Preparation of loweralkyl imidazole carboxylatesInfo
- Publication number
- CA1066709A CA1066709A CA245,697A CA245697A CA1066709A CA 1066709 A CA1066709 A CA 1066709A CA 245697 A CA245697 A CA 245697A CA 1066709 A CA1066709 A CA 1066709A
- Authority
- CA
- Canada
- Prior art keywords
- imidazole
- phenylethyl
- acid
- carboxylate
- carboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Imidazole carboxylates of the formula:
and the stereochemical optical isomers thereof are disclosed.
These compounds have been found useful as short-acting hypnotic agents.
Imidazole carboxylates of the formula:
and the stereochemical optical isomers thereof are disclosed.
These compounds have been found useful as short-acting hypnotic agents.
Description
: , . .
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, , 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' ' ~ , . ~ . . ~ . . . . .. .
.. . . . , . ~ , , 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 ' ', " ''- ~ ' ' ', ,,. ' `' , ' ' ,'; . , .` , ' .. ;~ -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- : :
~"' ..
" : .
- 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 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_ .
, .. .. . . , "., . ' . , .
.. .. . .. .. .. . .
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 .. . . .
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 ;~
-, ' ! . , ' . . ~ : , . , , , , :, . ' ' -," ' . .. ~ .. . ' ,, ~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-
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, , 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' ' ~ , . ~ . . ~ . . . . .. .
.. . . . , . ~ , , 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 ' ', " ''- ~ ' ' ', ,,. ' `' , ' ' ,'; . , .` , ' .. ;~ -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- : :
~"' ..
" : .
- 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 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_ .
, .. .. . . , "., . ' . , .
.. .. . .. .. .. . .
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 .. . . .
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 ;~
-, ' ! . , ' . . ~ : , . , , , , :, . ' ' -," ' . .. ~ .. . ' ,, ~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 ~ ~ ,................. . . . .
;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).
.. _ ...... ...... . . .. . -~, . , -- .
: , ' `.~ ' ~' " ' '' -', . ' . ~ . - .
, . ~ . , .. ~ .. . ... .. . .
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.
- . ,: . . , - . , , Jo~ o ~ ,............. ......................................................
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 .
, ' 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.
" . . . ~ . ~ ~ - . . -. , - . : -. - - : .
JJ~ 150 EX~ PLE III
A. To a stirred mixture of 40 parts of ethanol and
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 ~ ~ ,................. . . . .
;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).
.. _ ...... ...... . . .. . -~, . , -- .
: , ' `.~ ' ~' " ' '' -', . ' . ~ . - .
, . ~ . , .. ~ .. . ... .. . .
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.
- . ,: . . , - . , , Jo~ o ~ ,............. ......................................................
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 .
, ' 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.
" . . . ~ . ~ ~ - . . -. , - . : -. - - : .
JJ~ 150 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)-- ~ ' ',~ ' .
.
.
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).
.. . . .
: . . . .
. ; . . , - ' '~ ' . , .
. " , ' , ' ' ' ~' .
:
, .
'' ', , ~ ~
.
. .
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 , .. .
. , . . ;.. _ .. . .
'~ ' ,. ' , ~ , ' . . - - . " , ' i ' ' ' ' ' ' , ' ' ' ,: .
- ` ~ .. ...
.
-: r 1 - . ... . .
.~
., .
. , . ' . ,`', . - 20 -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 , .. : . . . .: .: .. , ~ ., . . . - -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 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
. . . ` `~ .
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 ~ .- .................. 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.
.~ ~ . , .
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,. .,: " . ~- . .. . -.
J ~ I 50 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-.. . . ..
.. . . . .
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 '' . . .
,~
: ' .
. :.
!,~ ,, ' , ~ .
..
.. : ...... . : .
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)-- ~ ' ',~ ' .
.
.
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).
.. . . .
: . . . .
. ; . . , - ' '~ ' . , .
. " , ' , ' ' ' ~' .
:
, .
'' ', , ~ ~
.
. .
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 , .. .
. , . . ;.. _ .. . .
'~ ' ,. ' , ~ , ' . . - - . " , ' i ' ' ' ' ' ' , ' ' ' ,: .
- ` ~ .. ...
.
-: r 1 - . ... . .
.~
., .
. , . ' . ,`', . - 20 -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 , .. : . . . .: .: .. , ~ ., . . . - -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 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
. . . ` `~ .
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 ~ .- .................. 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 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-.. . . ..
.. . . . .
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 '' . . .
,~
: ' .
. :.
!,~ ,, ' , ~ .
..
.. : ...... . : .
Claims (18)
1. A process of preparing an optically active lower-alkyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate which comprises resolving (?)-1-(1-phenylethyl)-1H-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 consisting of 1-phenylethylamine,1-(1-naphthyl)ethylamine and 1-(2-naphthyl)ethylamine in an inert organic solvent, mech-anically separating the insoluble optically active 1-(1-phenyl-ethyl)-1H-imidazole-5-carboxylic acid 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 1-(1-phenylethyl) -1H-imidazole-5-carboxylic acid with a loweralkyl esterifying agent directly, or first preparing the acid chloride before esterifying to yield optically active loweralkyl 1-(1-phenyl-ethyl)-1H-imidazole-5-carboxylate substantially free of the isomer of opposite sign.
2. A process of preparing (-)-loweralkyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate which comprises resolving (?)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid by mixing said acid with the (-)-isomer, substantially free of the (+)-isomer, of a base selected from the group consisting of 1-phenylethylamine, 1-(1-naphthyl)ethylamine and 1-(2-naphthyl)ethylamine in an inert organic solvent, mechanically separating the insoluble (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid (-)-base salt, treating said (-)-acid (-)-base salt with a strong non-oxidizing mineral acid and esterifying the thus-obtained (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid with a lower-alkyl esterifying agent to yield (-)-loweralkyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate substantially free of the (+)-isomer.
3. The process of preparing (-)-ethyl 1-(1-phenyl-ethyl)-1H-imidazole-5-carboxylate which comprises resolving (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid by mixing said acid with (-)-1-phenylethylamine, substantially free of the (+)-isomer in a loweralkanol solvent, mechanically separ-ating the insoluble (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid (-)-1-phenylethylamine salt, treating said (-)-acid (-)-base salt with a strong non-oxidizing mineral acid and esterifying the thus-obtained (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid to yield (-)-ethyl 1-(1-phenyl-ethyl)-1H-imidazole-5-carboxylate substantially free of the (+)-isomer.
4 . A process of preparing (+)-loweralkyl 1-(phenylethyl)-1H-imidazole-5-carboxylate which comprises resolving (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid by mixing said acid with the (+)-isomer, substantially free of the (-)-isomer, of a base selected from the group consisting of 1-phenylethylamine, 1-(1-naphthyl)ethylamine and 1-(2-naphthyl)ethylamine in an inert organic solvent, mechanically separating the insoluble (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid (+)-base salt, treating said (+)-acid (+)-base salt with a strong non-oxidizing mineral acid and esterirying the thus-obtained (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid with a lower-alkyl esterifying agent to yield (+)-loweralkyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate substantially free of the (-)-isomer.
5. The process of preparing (+)-ethyl 1-(1-phenyl-ethyl)-1H-imidazole-5-carboxylate which comprises resolving (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid by mixing said acid with (+)-1-phenylethylamine, substantially free of the (-)-isomer, in a loweralkanol solvent, mechanically separating the insoluble (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid (+)-1-phenylethylamine salt, treating said (+)-acid (+)-base salt with a strong non-oxidizing mineral acid and esterifying the thus-obtained (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid to yield (+)-ethyl 1-(1-phenyl-ethyl)-1H-imidazole-5-carboxylate substantially free of the (-)-isomer.
6. A process of preparing (-)-loweraltcyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate which comprises reacting a member selected from the group consisting of (-)-1-(1-phenylethyl)-1H-imidazole-5-carbonyl chloride and acid addition salts thereof with a loweralkanol and separating the thus-obtained (-)-loweralkyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate from the reaction mixture.
7 . A process of Claim 6 wherein said loweralkanol is a member selected from the group consisting of methanol, ethanol and propanol
8 . A process of preparing (+)-loweralkcyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate which comprises reacting a member selected from the group consisting of (+)-1-(1-phenylethyl)-1H-imidazole-5-carbonyl chloride and acid addition salts thereof with a loweralkanol and separating the thus-obtained (+)-loweralkyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate from the reaction mixture.
9.A process of Claim 8 whcrein said loweralkanol is a member selected from the group consisting of methanol, ethanol and propanol.
10. A process of preparing (-)-loweralkyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate which comprises re-solving (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid by mixing said acid with the (-)-isomer, substantially free of the (+)-isomer, of a base selected from the group con-sisting of 1-phenylethylamine, 1-(1-naphthyl)ethylamine and 1-(2-naphthyl)ethylamine in a inert organic solvent, mech-anically separating the insoluble (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid (-)-base salt, treating said (-)-acid (-)-base salt with a strong non-oxidizing mineral acid, transforming the hydroxy function of the thus-obtained (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid to a chloro function and treating the resultant (-)-1-(1-phenyl-ethyl)-1H-imidazole-5-carbonyl chloride with a loweralkanol to yield (-)-loweralkyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate substantially free of the (+)-isomer.
11. A process of preparing (-)-ethyl 1-(1-phenyl-ethyl)-1H-imidazole-5-carboxylate which comprises resolving (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid by mixing said acid with (-)-1-phenylethylamine, substantially free of the (+)-isomer, in a loweralkanol solvent, mechanically separating the insoluble (-)-1-(1-phenylethyl)-1H-imidazole -5-carboxylic acid (-)-1-phenylethylamine salt, treating said (-)-acid (-)-base salt with a strong non-oxidizing mineral acid, transforming the hydroxy function of the thus-obtained (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid to a chloro function by reacting said acid with thionyl chloride, and treating the resultant (-)-1-(1-phenylethyl)-1H-imidazole-5-carbonyl chloride with ethanol to yield (-)-ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate sub-stantially free of the (+)-isomer.
12. A process of preparing (+)-loweralkyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate which comprises re-solving (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid by mixing said acid with the (+)-isomer, substantially free of the (-)-isomer, of a base selected from the group consisting of 1-phenylethylamine, 1-(1-naphthyl)ethylamine and 1(2-naphthyl)ethylamine in an inert organic solvent, mechanically separating the insoluble (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid (+)-base salt, treating said (+)-acid (+)-base salt with a strong non-oxidizing mineral acid, trans-forming the hydroxy function of the thus-obtained (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid to a chloro func-tion and treating the resultant (+)-1-(1-phenylethyl)-1H-imidazole-5-carbonyl chloride with a loweralkanol to yield (+)-loweralkyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate substantially free of the (-)-isomer.
13 . A process of preparing (+)-ethyl 1-(1-phenylethyl)-1-H-imidazole-5-carboxylate which comprises resolving (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid by mixing said acid with (+)-1-phenylethylamine, substantially free of the (-)-isomer in a loweralkanol solvent, mechanically separating the insoluble (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid (+)-1-phenylethylamine salt, treating said (+)-acid (+)-base salt with a strong non-oxidizing mineral acid, transforming the hydroxy function of the thus-obtained (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid to a chloro function by reacting said acid with thionyl chloride and treating the resultant (+)-1-(1-phenylethyl)-1H-imidazole-5-carbonyl chloride with ethanol to yield (+)-ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate substantially free of the (-)-isomer.
14. Loweralkyl 1-(phenylethyl)-1H-imidazole-5-carb-oxylate whenever prepared or produced by the process of claim 1 or by their obvious chemical equivalents.
15. (-)-loweralkyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate whenever prepared or produced by the process of claim 2, 6 or 10 or by their obvious chemical equivalents.
16. (-)-ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxy-late whenever prepared or produced by the process of claims 3 or 11 or by their obvious chemical equivalents.
17. (+)-loweralkyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate whenever prepared or produced by the process of claims 4, 8 or 12 or by their obvious chemical equivalents.
18. (+)-ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxy-late whenever prepared or produced by the process of claims 5 or 13 or by their obvious chemical equivalents.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US55719475A | 1975-03-10 | 1975-03-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1066709A true CA1066709A (en) | 1979-11-20 |
Family
ID=24224401
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA245,697A Expired CA1066709A (en) | 1975-03-10 | 1976-02-13 | Preparation of loweralkyl imidazole carboxylates |
Country Status (27)
| Country | Link |
|---|---|
| JP (1) | JPS51115473A (en) |
| AT (1) | AT353262B (en) |
| AU (1) | AU503733B2 (en) |
| BE (1) | BE839120A (en) |
| BG (1) | BG24806A3 (en) |
| CA (1) | CA1066709A (en) |
| CH (1) | CH629192A5 (en) |
| CS (1) | CS203116B2 (en) |
| DE (1) | DE2609573A1 (en) |
| DK (1) | DK99376A (en) |
| ES (1) | ES445450A1 (en) |
| FI (1) | FI62292C (en) |
| FR (1) | FR2318159A1 (en) |
| GB (1) | GB1535566A (en) |
| HU (1) | HU172026B (en) |
| IE (1) | IE42652B1 (en) |
| IL (1) | IL49190A (en) |
| IT (1) | IT1057941B (en) |
| LU (1) | LU74503A1 (en) |
| NL (1) | NL7602444A (en) |
| NO (1) | NO144884C (en) |
| PL (1) | PL99926B1 (en) |
| PT (1) | PT64879B (en) |
| SE (1) | SE7601959L (en) |
| SU (1) | SU677656A3 (en) |
| YU (1) | YU60876A (en) |
| ZA (1) | ZA761427B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9156825B2 (en) | 2012-01-13 | 2015-10-13 | The General Hospital Corporation | Anesthetic compounds and related methods of use |
| US9181197B2 (en) | 2008-03-31 | 2015-11-10 | The General Hospital Corporation | Etomidate analogues with improved pharmacokinetic and pharmacodynamic properties |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE871675A (en) * | 1977-12-02 | 1979-04-30 | Smithkline Corp | PROCESS FOR PREPARING DERIVATIVES OF IMIDAZOLE |
| JPS5671073A (en) | 1979-11-12 | 1981-06-13 | Takeda Chem Ind Ltd | Imidazole derivative |
| JPS5671074A (en) | 1979-11-12 | 1981-06-13 | Takeda Chem Ind Ltd | 1,2-disubstituted-4-halogenoimidazole-5-acetic acid derivative |
| JPS58157768A (en) * | 1982-03-16 | 1983-09-19 | Takeda Chem Ind Ltd | 4-chloro-2-phenylimidazole-5-acetic acid derivative |
| PL149675B1 (en) * | 1986-03-10 | 1990-03-31 | Method of obtaining novel derivatives of 1-methyl 1h-imidazolecarboxylic-5 acid | |
| RU2144022C1 (en) * | 1995-10-30 | 2000-01-10 | Такеда Кемикал Индастриз, Лтд. | N-(biphenylmethyl)aminobenzoic acid esters and method of their synthesis |
-
1976
- 1976-02-13 CA CA245,697A patent/CA1066709A/en not_active Expired
- 1976-02-18 GB GB6339/76A patent/GB1535566A/en not_active Expired
- 1976-02-19 SE SE7601959A patent/SE7601959L/en not_active Application Discontinuation
- 1976-02-23 ES ES445450A patent/ES445450A1/en not_active Expired
- 1976-03-01 FR FR7605762A patent/FR2318159A1/en active Granted
- 1976-03-03 BE BE164793A patent/BE839120A/en not_active IP Right Cessation
- 1976-03-05 CH CH280676A patent/CH629192A5/en not_active IP Right Cessation
- 1976-03-08 LU LU74503A patent/LU74503A1/xx unknown
- 1976-03-08 DE DE19762609573 patent/DE2609573A1/en not_active Withdrawn
- 1976-03-08 IT IT48460/76A patent/IT1057941B/en active
- 1976-03-08 NO NO760790A patent/NO144884C/en unknown
- 1976-03-08 JP JP51024280A patent/JPS51115473A/en active Pending
- 1976-03-08 CS CS761495A patent/CS203116B2/en unknown
- 1976-03-08 DK DK99376*#A patent/DK99376A/en not_active Application Discontinuation
- 1976-03-09 PT PT64879A patent/PT64879B/en unknown
- 1976-03-09 HU HU76JA00000750A patent/HU172026B/en unknown
- 1976-03-09 AT AT171776A patent/AT353262B/en not_active IP Right Cessation
- 1976-03-09 NL NL7602444A patent/NL7602444A/en not_active Application Discontinuation
- 1976-03-09 IE IE482/76A patent/IE42652B1/en unknown
- 1976-03-09 AU AU11806/76A patent/AU503733B2/en not_active Expired
- 1976-03-09 ZA ZA761427A patent/ZA761427B/en unknown
- 1976-03-09 YU YU00608/76A patent/YU60876A/en unknown
- 1976-03-09 FI FI760601A patent/FI62292C/en not_active IP Right Cessation
- 1976-03-10 IL IL49190A patent/IL49190A/en unknown
- 1976-03-10 BG BG032575A patent/BG24806A3/en unknown
- 1976-03-10 PL PL1976187827A patent/PL99926B1/en unknown
- 1976-03-10 SU SU762329945A patent/SU677656A3/en active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9181197B2 (en) | 2008-03-31 | 2015-11-10 | The General Hospital Corporation | Etomidate analogues with improved pharmacokinetic and pharmacodynamic properties |
| US9156825B2 (en) | 2012-01-13 | 2015-10-13 | The General Hospital Corporation | Anesthetic compounds and related methods of use |
| US9522136B2 (en) | 2012-01-13 | 2016-12-20 | The General Hospital Corporation | Anesthetic compounds and related methods of use |
| US9820971B2 (en) | 2012-01-13 | 2017-11-21 | The General Hospital Corporation | Anesthetic compounds and related methods of use |
| US10154991B2 (en) | 2012-01-13 | 2018-12-18 | Annovation Biopharma, Inc. | Anesthetic compounds and related methods of use |
Also Published As
| Publication number | Publication date |
|---|---|
| IT1057941B (en) | 1982-03-30 |
| PT64879B (en) | 1978-02-06 |
| ES445450A1 (en) | 1977-10-16 |
| BE839120A (en) | 1976-09-03 |
| NL7602444A (en) | 1976-09-14 |
| SU677656A3 (en) | 1979-07-30 |
| CS203116B2 (en) | 1981-02-27 |
| AU503733B2 (en) | 1979-09-20 |
| SE7601959L (en) | 1976-09-13 |
| BG24806A3 (en) | 1978-05-12 |
| IE42652L (en) | 1976-09-10 |
| AU1180676A (en) | 1977-09-15 |
| IE42652B1 (en) | 1980-09-24 |
| ATA171776A (en) | 1979-04-15 |
| FI62292C (en) | 1982-12-10 |
| GB1535566A (en) | 1978-12-13 |
| HU172026B (en) | 1978-05-28 |
| ZA761427B (en) | 1977-10-26 |
| FR2318159A1 (en) | 1977-02-11 |
| IL49190A (en) | 1980-07-31 |
| DE2609573A1 (en) | 1976-09-30 |
| YU60876A (en) | 1983-01-21 |
| PL99926B1 (en) | 1978-08-31 |
| IL49190A0 (en) | 1976-05-31 |
| FR2318159B1 (en) | 1979-07-27 |
| NO144884C (en) | 1981-12-02 |
| NO144884B (en) | 1981-08-24 |
| LU74503A1 (en) | 1976-09-01 |
| JPS51115473A (en) | 1976-10-12 |
| PT64879A (en) | 1976-04-01 |
| DK99376A (en) | 1976-09-11 |
| CH629192A5 (en) | 1982-04-15 |
| NO760790L (en) | 1976-09-13 |
| FI62292B (en) | 1982-08-31 |
| AT353262B (en) | 1979-11-12 |
| FI760601A7 (en) | 1976-09-11 |
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