NO137233B - ANALOGICAL PROCEDURES FOR THE PREPARATION OF THERAPEUTIC ACTIVE ALFA, ALFA-DIARYLIMIDAZOLE-2-METHANOLS AND ACID ADDITIONAL SALTS THEREOF. - Google Patents

Description

The present invention relates to the production of

new therapeutically usable α,α-diarylimidazole-2-methanols as well as acid addition salts thereof.

The new α,α-diarylimidazole-2-methanols which. manufacture

read according to the invention, they are of the general formula:

where R-l~R-|_o are -^^e or different and each means a hydrogen-

or halogen atom or a trifluoromethyl or tertiary butyl group,

provided that at least one of them is halogen, trifluoromethyl or tertiary butyl, R-^ and R^2 are the same or different and each represents a hydrogen atom, a lower alkyl group, a phenyl group or a halogen-substituted phenyl group and R-^ represents a hydrogen atom or a lower alkyl group, a lower alkoxymethyl group, a phenyl-lower-alkyl group (optionally substituted in the phenyl part with a halogen atom), a lower alkenyl group, a phenyl-lower-alkyl-

methyl group or a toluene-p-sulfonyl group. The term "lower"

as used with respect to the alkyl and alkoxy groups, implies that the groups contain no more than 6 carbon atoms.

The α,α-diarylimidazole-2-methanols of the general formula

It has valuable therapeutic properties. They show anorexic

effect. Within the group of compounds defined by the formula I, those in which means a hydrogen atom or, when R^

and R 2 are hydrogen atoms or one or both of them is a lower alkyl group, a lower alkoxymethyl group or a phenyl-lower-alkoxymethyl group, analgesic action which makes the compounds useful for alleviating pain in humans and animals. They also have antiphlogistic and antipyretic effects.

As compounds with anorexic action are the compounds of the formula I in which R is different from hydrogen and, when R

and R 2 are hydrogen atoms or one or both is an alkyl group, from alkyloxymethyl or phenyl-lower-alkyloxymethyl, preferably.

The most active compounds are those in which Rq and Rg are both a chlorine atom, R^ and R-^ are hydrogen atoms or one of them is a £-chlorophenyl group and R-^ R2 > R^, R^, Rg, R^, R ^ and R1Q are hydrogen atoms. Particularly preferred compounds are α,α-bis(β-chlorophenyl)-1-vinylimidazole-2-methanol and 1-benzyl-α,α-bis(β-chlorophenyl)imidazole-2-methanol and salts thereof.

Within the group of analgesically active compounds indicated above, the preferred compounds are those in which R^ is a halogen atom or a trifluoromethyl or tertiary butyl group, Rg is a hydrogen or halogen atom or a trifluoromethyl or tertiary butyl group and Rj, R2, R^, R^ , Rg, Ry, Rg, R1Q, R-q and R12 are hydrogen atoms. Particularly preferred are the compounds in which both R 1 and R 2 are a chlorine atom or R 2 is a trifluoromethyl group and R 2 is a hydrogen atom. The most active and therefore most preferred compounds are α,α-bis(α-chlorophenyl)imidazole-2-methanol, α,α-bis(α-chlorophenyl)-1-methoxy-methylimidazole-2-methanol, α-phenyl- α-(£-trifluoromethylphenyl)imidazole-2-methanol and 1-(methoxymethyl)-α-phenyl-ou (£-trifluoromethylphenyl)imidazole-2-methanol.

Analgesic substances are usually divided into two main groups according to the type of action shown. According to their best known properties, these groups are usually designated as (a) morphine-type analgesics and (b) aspirin-type analgesics.

Analgesics of the first type show stronger effects, but are known to have significant, sometimes serious, shortcomings due to side effects such as sedation, respiratory depression, debility, physical dependence and indigestion. Analgesics of the second type are also known to cause side effects which, due to the wide spectrum of compound structures usually classified within this group, can vary from stomach damage for salicylic acid derivatives to agranulocytosis for aminopyrine.

The analgesic action of the compound of formula I

is clearly confirmed from results obtained in one or more of the following tests: (a) Experiments according to Carrol and Lim using rats (M.V. Carrol and

R.K.S. Lim, "Archiv. int. Pharmacodyn", 12^, 383 (I96O));

(b) Experiment according to Randall and Selitto using rats (L.O. Randall

and J.J. Selitto, "Archiv. int. Pharmacodyn.", 111, 409,419

(1957))<;>

(c) Experiment according to d'Amour and Smith (tail flick), using rats

(F.E. d'Amour and D.I. Smith, "J. Pharm. Exp. Therap.", J2,

74-79 (194D);

(d) Hot plate test using mice (G. Woolfe and A.D. Macdonald,

"J. Pharmacol. Exptl. Ther.", 80, 300-307 (1944)).

Experiment (a) enables some differentiation between morphine-type vis-a-vis aspirin-type analgesics; in experiment (b) analgesics of both types show an effect; experiment (c) gives positive results for very strong analgesics such as morphine; attempt (d) is not very specific. In all of the above-mentioned tests, the compounds indicated above as preferred analgesics show strong activity both by oral and parenteral administration.

The following results were obtained with α,α-bis(p-chloro-phenyl)imidazole-2-methanol (hereinafter referred to as "Compound A").

The AD-^QQ dose (ie the dose that raises the pain threshold

with 100%) for compound A in Randall-Selitto tests is 3>4 mg/kg body weight for animals when administered orally (p.o.); The ED^Q dose (ie

the dose protecting 50% of rats) for compound A in the d'Amour-Smith test is 21 mg/kg animal body weight (p.o.); for morphine is

the 45 mg/kg (p.o.).

(e) A special test has been carried out with α,α-bis(p_-chloro-phenyl)imidazole-2-methanol to determine whether the compound can cause physical dependence: Test according to Saelens et al. (J.K. Saelens et al., "Arch. int. Pharmacodyn", 130 (2), 213-218 (197D) '.provides a rapid test of potential physical dependence as found for morphine.

When compound A is compared with a number of analgesics belonging to the morphine type, the results were positive for these analgesics and negative for compound A.

The following observation tests have been carried out for

determine whether the compound causes certain side effects that accompany the administration of morphine:

(f) Observation of the behavior of dogs when administering an analgesic. Morphine is known to cause vomiting in dogs and also to cause respiratory depression. None of these reactions were caused by compound A. However, a slight stimulation and antagonism of narcosis and narcosis-induced respiratory depression was observed after administration of the compound. (g) Observation of the behavior of cats upon administration of an analgesic. Morphine causes such excitement in cats that they are completely uncontrollable; such arousal was not at all caused by the administration of compound A. (h) Observation of the behavior of rats upon the administration of an analgesic. Morphine sedates rats, but activation is noted when compound A is administered.

The analgesic power of most active α,α-diaryl-imidazole-2-methanols according to the invention is comparable to that of morphine; however, as the compound does not show the serious side effects of morphine, it should not be called "morphine-like". Possibly they should be classified in a third class.

For use as therapeutics, the compounds of the general formula I can either be used as such or as non-toxic acid addition salts, i.e. salts which are not harmful to the organism when used in therapeutic doses. Such acid addition salts can be derived from inorganic acids such as hydrohalic acids (e.g. hydrochloric acid and hydrobromic acid) and sulfuric acid, and further organic acids such as oxalic acid, maleic acid, tartaric acid, citric acid, acetic acid, lactic acid, succinic acid, fumaric acid and pamoic acid.

The dosage and method of administration will depend on the mammal species and the condition treated. For use as an agent with an anorexic effect in adults, the oral dose will be from 25 to 200 mg per person daily. The compounds with analgesic action are conveniently administered orally to humans in daily doses of from 5 to 100 mg per person. Injectable solutions for analgesic purposes will usually have a concentration in the range of 0.5 to 2 mg/ml.

The α,α-diaryl-imidazole-2-methanols of the general formula I are prepared by reacting a compound of the general formula:

(where R-j^ means an alkali metal (preferably lithium) atom or a reactive organo-metallic group such as MgX, where X means halogen (preferably chlorine or bromine), R-^ is identical to R-^ except for a hydrogen atom, or a group beyond the scope of R^ which is readily f ironable, for example by hydrolysis, oxidation or hydrogenation, and R-q and R-^ are as described above) with a compound of the general formula:

wherein R^-Rio is as described above, and then removing the group or atom R-^ from the resulting organometallic complex by hydrolysis to obtain a desired tertiary alcohol of the general formula I wherein R-^ represents a hydrogen atom or a similar compound which carries a substituent in the group R-^ on a nitrogen atom in the imidazole nucleus and, when in the latter case the substituent group is not identical to R-^ in the desired product, in ways known per se to remove said substituent group and, if desired, to introduce a group within the definition of R-^ in a manner known per se. The reaction between the compound of formula II and III is preferably carried out in an inert anhydrous organic solvent (eg tetrahydrofuran) or a solvent mixture (eg tetrahydrofuran and diethyl ether). When R-1 means an alkali metal atom, it is preferred to carry out the reaction at a temperature below 0°C; when R-^ means a group MgX, a solution of the reactants is preferably boiled under reflux.

It should be obvious that the definition of R-^ includes removable groups that are covered by the definition for R-^ and that when R-^ is such a group then the compound obtained from the reaction of compounds of formula II and III can both be an intermediate and a

final product.

Examples of easily removable groups represented by R-^ in compounds of the general formula II are toluene-p-sulfonyl, benzyloxymethyl and alkoxyalkyl groups, and the methoxymethyl group is preferred. Such groups can all be removed by hydrolysis to thereby obtain compounds of the general formula I where R-^ denotes a hydrogen atom.

The hydrolytic removal of the group R-^ can occur spontaneously when the product resulting from the reaction between compounds of the general formulas II and III is hydrolyzed. Active removal of a group R-^ by hydrolysis can take place by heating in aqueous solution a resulting tertiary alcohol with the general formula:

(where the various symbols are as described above) to which some acid or base has been added.

When R-j^ is a group which can be removed by oxidation, e.g. allyl, vinyl or prop-1-enyl, the group can be removed from the resulting tertiary alcohol by oxidation with a permanganate, e.g. potassium permanganate, to which some aqueous alkali hydroxide solution has been added. Removal of the allyl group by oxidation is only possible when the double bond has previously been shifted to the a-position (ie the allyl group has become prop-l-enyl). In some cases, the shift occurs simultaneously with the introduction of the substituent R-1 in the appropriate imidazole compound to obtain a compound of formula II, especially in those cases where R-1 represents a lithium atom. Otherwise, the shift must be effected by treatment in advance with a strong base, e.g. potassium tertiary butoxide in an organic solvent, e.g. dimethyl sulfoxide.

When. R-^ means a benzyl group, its removal can be effected by hydrogenation... Substances suitable for hydrogenation (e.g. sodium with liquid ammonia) can act on any halogen substituent on the phenyl nucleus. Generally speaking, such half-gen atoms are the more tightly bound the lower the atomic number and it follows that the use of the benzyl group as a protecting group is only recommended when the symbols and/or R~ means a fluorine atom or a trifluoromethyl or tert-butyl group.

The introduction of a group R-^ in a compound of the formula I in which R-^ is a hydrogen atom is preferably carried out by reacting the compound of the formula I with a suitable alkyl-, alkoxymethyl-, substituted or unsubstituted phenylalkyl-, alkenyl-, phenylalkoxy- methyl or substituted or unsubstituted toluene p-sulfonyl halide. such as a chloride or bromide. The reaction is preferably carried out in an organic solvent in the presence of a base (eg sodium hydroxide) and a catalytic excess of sodium iodide or potassium iodide.

The compounds of the general formula II where R-^ means a lithium atom can be prepared by reacting under a nitrogen atmosphere a lithium-donating compound, e.g. butyllithium, with a compound of the general formula:

wherein R 11 , R 12 and R 14 are as defined above. The reaction is preferably carried out in an inert, anhydrous, organic solvent (e.g. tetrahydrofuran) or solvent mixture (e.g. a mixture of tetrahydrofuran and diethyl ether). Such compounds of the general formula II can be prepared in situ from compounds of the general formula V; and they are immediately reacted with a compound of the general formula III without prior isolation or purification.

The choice of the groups B.^ is limited to those groups which are not capable of reacting with atoms or groups represented

at Rq_5* When R-^ or R-^ is a substituted or unsubstituted phenyl group, compounds of the formula I in which R-^ is a hydrogen atom can be easily decomposed by hydrolysis. The use of a protective group R-^ which is to be removed by hydrolysis should therefore be avoided in such cases.

Furthermore, the connections can with

the general formula I is prepared by reacting a compound of the general formula:

(where R^' is a hydrogen atom or a group within the definition of R-j^ and R-j^ and the other R symbols are as described above)- with a compound of the general formula

(where the R symbols are as described above), preferably under reaction conditions corresponding to those described above for the reaction of compounds of formulas II and III, by removing the atom or group R-^ from the resulting organo-metallic complex by hydrolysis and if desired to replace R]_^' with a substituent within the definition of R-^ as described above.

The starting substances with the formula VI can be prepared by reacting a compound with the general formula:

where !R^g means an alkali metal ;(:preferably lithium) atom or :a group .MgX .(where .X means a halogen., preferably :chlorine or bromine) and R-^., R 12 and .are as described. .above,, .with .a :n±.tr.'il ;with the general :f orméL: where Rg-R-^Q is as described above, and if desired to remove the group ^14 and ^ i'introduce one group ^2.3' vec* ^JelP of methods' which are: described above. Preferred reaction conditions are those described for the reaction between compounds of the formulas II and III when -R-^ in the non-formula II means an alkali metal atom or a group MgX.

Furthermore, α,α-bis-arylimidazole-,2-methanols with the general formula I are produced, which

is .symmetrically .substituted in the :phenyl gimpp.ene, i.e.,, -the compounds with it

.general if.ormél':

where the different R symbols are as described above and at least one of R-|_-, R2 > R^, R^ and :R^ is halogen, trifluoromethyl or tertiary v.util,

.by converting a compound with the general formula:

where R-^ rj means a halogen atom, an alkoxy-, aryloxy-, aralkyl-

or silyloxy, e.g., trimethylsiloxy group or a group OM

wherein M is a metal atom and R-q> R-^°S R]_^ is as described above, with a compound of the general formula VII, hydrolyzing the resulting organo-metallic complex to obtain a desired tertiary alcohol with the general formula X wherein R-^ means a hydrogen atom or a corresponding compound which. carries a substituent group R-^

on a nitrogen atom in the imidazole nucleus, and when in the latter case the substituent group is not identical to the group R-^ in the desired product, in ways known per se to remove said substituent group and, if desired, to introduce a group within the definition of R^ 2 Pa i °g f°r seS known way. The reaction is preferably carried out by

■heating the compound of formula XI with twice the molar amount of the compound of formula VII in an inert, anhydrous, organic solvent. (eg. tetrahydrofuran and diethyl ether). The group R-^ can be removed as described above.

Compounds of the general formula XI can be prepared by reacting an imidazole derivative of the formula II where R-^ means a lithium atom, e.g. a compound of the general formula: where R-q» R^p and R-,^ are as described above, with a carbon dioxide to obtain a lithium salt of an imidazole-2-carboxylic acid of the general formula:

where R-j.1» R12 and ^14 are as described above, and if desired to convert the latter into another compound with the formula XI in a manner known per se. E.g. the compound of formula XIII can be reacted with an alkyl halide, aryl halide or aralkyl halide to obtain an alkyl, aryl or aralkyl ester (R-|_y = alkoxy, aryloxy or aralkyloxy), with a halosilane to obtain a silyl ester (R]_y = silyloxy) or with a thionyl halide to obtain an acid halide (R^y = halogen).

It should be clear that the double bond when R-^ means

an allyl group, can be changed to the cx-position simultaneously with the preparation of the compound of formula XII as described above for compounds of formula II.

When R-j^ denotes an alkoxy, aryloxy or aralkyl group, the compound of formula XI can also be prepared by reacting a compound of formula V with a halogen formate of the general formula:

where Hal means a halogen atom and R-^g means an alkyl, aryl or aralkyl group. The reaction is preferably carried out by heating the reactants in a polar solvent such as dimethylformamide or acetonitrile, in the presence of a strong base, e.g. triethylamine.

Furthermore, the compounds are produced with

the formula I in which R,, is a lower alkyl group, a

lower alkoxymethyl group, a phenylalkyl group (optionally substituted in the phenyl part by one or more halogen atoms or alkyl or trifluoromethyl groups), an alkenyl group, a phenyl(lower) alkoxymethyl group (optionally substituted in the phenyl part by one or more halogen atoms or alkyl or trifluoromethyl groups) or a

benzenesulfonyl group (in which the phenyl part is optionally substituted with one or more alkyl groups) by introduction in per se known ways of the substituent R-^ in the corresponding compound in which R-^

is a hydrogen atom. A suitable method is the reaction with a suitable halide as described above.

The following illustrative examples shall illuminate the invention in more detail.

Example I

A. Preparation of α-(p_-bromophenyl)-α-phenyl-1-(toluene-p_-sulfonyl)-imidazole-2-methanol.

To a solution of 33 > 3 g or 0.15 ml of 1-(toluene-p_-sulfonyl)imidazole (H.A. Staab and K. Wendel, "Ber.", 93 (1960) 2902) in 300 ml of anhydrous tetrahydrofuran and Into 50 ml of anhydrous diethyl ether at a temperature of -40° to -50°C, 91 ml of a 20 percent solution of 0.20 mol of butyllithium in n-hexane, dissolved in 150 ml of anhydrous diethyl ether, was added dropwise under a nitrogen atmosphere. At the end of the addition, the mixture was kept at a temperature of -40° to -50°C

for one hour. Then and under identical conditions with regard to temperature, 44>4 g or 0.17 mol of 4-bromobenzophenone in 200 ml of anhydrous tetrahydrofuran and 100 ml of anhydrous diethyl ether were added dropwise and the mixture was kept under the same conditions for a further 3>5 hours. Cooling was stopped and the mixture was allowed to reach ambient temperature for 1/2 hour. It was then poured into about 250 ml of a sodium chloride solution. The aqueous layer was separated and discarded and the organic solvent layers were washed with 100 ml of a sodium chloride solution, dried and concentrated. The residual oil was brought to crystallization by adding a very small amount of diethyl ether. Purification took place by crystallization from hot ethanol to which some acetone had been added. The melting point of the product was 138-140°C.

B. Preparation of α-(p-bromophenyl)-α-phenylimidol-2-methanol.

A mixture of 24.8 g or 0.052 mol of α-(p-bromophenyl)-α-phenyl--1-(toluene-β-sulfonyl)imidazole-2-methanol, 160 ml of 2N hydrochloric acid solution (0.156 mol) and about 500 ml of water was boiled under reflux for 5 hours. After cooling, the mixture was made alkaline by the addition of ammonia. The precipitated solid was collected, washed with activated carbon in boiling toluene and crystallized from toluene. The melting point of the product was 156-158°C.

EXAMPLE II

A. Preparation of α-α-bis(α-fluorophenyl)-1-(toluene-α-sulfonyl)-imidazole-2-methanol.

Using the method described in Example IA, but using an equivalent amount of 4>4'-difluorobenzophenone (J.P. Picard et .al., "Can. J.Res.", 28 B (1950), 56) instead of 4-bromobenzophenone, it was. obtained an oil from which the above-mentioned compound crystallized on the addition of some cold diethyl ether.

It was purified by boiling with petroleum ether (boiling range 40-60°C) and then, with diethyl ether followed by crystallization from ethanol. The melting point was 149-151°C.

B. Preparation of a,cc-bis(£-fluorophenyl)imidazole-2-methanol.

A mixture of 10 g or 0.0227 mol a,a-bis(£-fluoro--phenyl)-1-(toluene-£-sulfonyl)imidazole-2-methanol, 34 ml 2N hydrochloric acid solution (0.068l mol) and 225 ml of water was refluxed for 5 hours. After cooling, the mixture was made alkaline by the addition of ammonia. The base obtained was crystallized from isopropyl alcohol; melting point was 198-200°C.

EXAMPLE III

A. Preparation of α,α-bis(α-chlorophenyl)-1-(toluene-α-sulfonyl)-imidazole-2-methanol.

Using the method described in Example IA, but using an equivalent amount of 4i4'-dichlorobenzophenone instead of 4-bromobenzophenone, a reaction mixture was obtained which was poured into a mixture of acetic acid and water. The layer of organic

-solvents were separated, washed, dried and concentrated. The residual oil was brought to crystallization by adding some diethyl ether. The solid was separated and the filtrate concentrated and again subjected to the same treatment. This was repeated until five solid fractions had been obtained, the last three of which contained the desired product in impure form. They were repeatedly mixed and boiled with petroleum ether (boiling range 40-60°C). The final purification was carried out

led by crystallization from ethanol.. The melting point of the product was

•I5l-i53°c.

B. Preparation of α,α-bis(α-chlorophen<y>1)imidazole-2-methanol.

A mixture of 13 g of α,α-bis(α-chlorophen<y>l)-l-(toluene-α-sulfonyl)imidazole-2-methanol, 6 ml of concentrated hydrochloric acid solution, 6 ml of water and 60 ml of acetic acid was refluxed for 1.5 hours. The desired compound was crystallized from hot toluene containing kept a small amount of isopropyl alcohol and then from boiling diethyl ether to which some tetrahydrofuran had been added. The melting point of the product was 195-197°C. 15 g of the compound was dissolved in acetone and a solution of hydrogen chloride in ethanol was added. After adding a small amount of petroleum ether (boiling range 60-80°C), a precipitate consisting of the hydrochloride was obtained. The salt was washed with diethyl ether and crystallized from a mixture of ethanol and petroleum ether (boiling range 60-80°C). Melting point t was over 200°C during decomposition.

EXAMPLE IV

Preparation of α-(£-chlorophenyl)-α-phenylimidazole-2-methanol.

To 5>6 g of lithium in 150 ml of anhydrous diethyl ether, under a nitrogen atmosphere, 44>5 S butyl bromide in 100 ml of diethyl ether was added dropwise at a temperature of -10°C. After finished reaction '?. hours, the solution was filtered and added dropwise to 55>5 f;' 1-(toluene-£-sulfonyl)imidazole which was dissolved in 145 ml of anhydrous tetrahydrofuran and 225 ml of anhydrous diethyl ether at a temperature of -30°C. After 1 hour, 58.6 g of 4-chlorobenzophenone, dissolved in 300 ml of anhydrous tetrahydrofuran and 150 ml of anhydrous diethyl ether, was added dropwise at -30°C. The mixture was held at a temperature of -40° to -50°C for 3 hours, allowed to reach ambient temperature and then washed

twice with water. The organic solvent layers were concentrated and 500 ml of glacial acetic acid, 50 ml of 3% hydrochloric acid solution and 50 ml of water were added. The mixture was refluxed for 1.5

hours. Glacial acetic acid was removed as completely as possible and water and diethyl ether were added.

The ether layer containing unreacted ketone and the aqueous oily layer containing the desired compound as hydrochloride salt were separated. The aqueous layer was made alkaline by the addition of 2N sodium hydroxide solution and extracted with diethyl ether. The ether layer was acidified with 16% hydrochloric acid solution and extracted with water. The aqueous layer was treated with activated charcoal, made alkaline with 2N sodium hydroxide solution and extracted again with diethyl ether. The diethyl ether layer was dried and concentrated and the solid obtained was crystallized from isopropyl alcohol. The melting point of the product was 162-165°C.

EXAMPLE V

Preparation of α-(£-chlorophenyl)-α-phenylimidazole-2-methanol.

A solution of 17.2 g of 2-benzoylimidazole (A. Sonn and

P. Greif, "Ber.", 66, (1933), 1900) in 100 ml of anhydrous tetrahydrofuran was added dropwise to a Grignard compound prepared from 5.8 g of magnesium and 45 >9 g of 1-bromo-4- chlorobenzene in 150 ml anhydrous tetrahydrofuran. The reaction mixture was refluxed for 1/2 hour, cooled and poured onto a mixture of ice and hydrochloric acid. The solution was neutralized with concentrated ammonia solution and extracted with tetrahydrofuran. The organic solvent layer was dried and concentrated; the residue was crystallized from isopropyl alcohol. The melting point of the product was 162-165°C.

EXAMPLE VI

A. Preparation of 1-[(benzyloxy)methyl)imidazole.

To 58 g of imidazole sodium in 200 ml of anhydrous tetrahydrofuran, 100 g of benzylchloromethyl ether was added dropwise with stirring at a temperature of 0 to 5°C. The cooling was interrupted after one hour. The mixture was left overnight and then concentrated. The residue was treated with 2N hydrochloric acid solution and with diethyl ether. The acidic aqueous layer was made alkaline with potassium carbonate and extracted with chloroform. The chloroform layer was treated with activated charcoal, dried and concentrated. The residue was subjected to distillation, the boiling point was 147°C at 3 ^ Hg.

B. Preparation of 1-((benzyloxy)methyl]-α-(β-chlorophenyl)-α-phenyl-imidazole-2-methanol.

To a solution of 11.8 g of 1-((benzyloxy)methyl)-imidazole in 100 ml of anhydrous tetrahydrofuran and 50 ml of anhydrous diethyl ether was added a solution of 38 g of a 20 percent butyllithium suspension in hexane, dissolved in 75 ml anhydrous diethyl ether, dropwise with stirring at room temperature. Then, a solution of 14.6 g of 4-chlorobenzophenone in 100 ml of anhydrous tetrahydrofuran and 50 ml of anhydrous diethyl ether was added dropwise at room temperature. The mixture was kept thus for 3 hours and then extracted with a dilute acid solution. The acidic aqueous layer was made alkaline with 2N sodium hydroxide solution and extracted with diethyl ether. Part of the ether was removed by evaporation and the remainder washed with water. The ether solution was again concentrated and the desired compound crystallized from a mixture of toluene and petroleum ether (boiling range 28-40°C) The melting point of the product was 114.5-117° C. Preparation of c-(p-chlorophenyl)-α-phenylimidazole-2-methanol.

About 17 g or 0.042 mol of 1-((benzyloxy)methyl)-α-(p_-chlorophenyl)-α-phenylimidazole-2-methanol was refluxed in a mixture of 85 ml of glacial acetic acid, 8.5 ml of water and 8, 5 ml of concentrated hydrochloric acid solution. Acetic acid was removed by evaporation and the base was set free by the addition of 2N sodium hydroxide solution. It was crystallized from isopropyl alcohol. The melting point of the product was 162-165°C.

EXAMPLE VII

A. Preparation of α,α-bis(p-chlorophenyl)-1-(methoxymethyl)-imidazole-2-methanol.

To a solution of 11.2 g or 0.1 mol l-(methoxy-

, methyl)-imidazole and 13.9 g or 0.12 mol of N,N,N',N'-tetramethylethylenediamine in 150 mol of anhydrous tetrahydrofuran, 51 ml or 0.12 mol of n-butyllithium solution in hexane was added while stirring in a period of about one hour and at a temperature of -60°C. Stirring was continued for a further 2 hours at -60°C. The cooling was stopped and 25.1 g or 0.1 mol of 4'4'-dichlorobenzophenone in 150 ml of anhydrous tetrahydrofuran was added dropwise. The mixture was stirred for 6 hours at room temperature and decomposed by the addition of 15 ml of water. Lithium hydroxide was removed by filtration and the filtrate was concentrated. A 2N hydrochloric acid solution was added and the mixture was extracted with smaller amounts of diethyl ether. The acidic anhydrous solution was made alkaline by the addition of potassium carbonate and extracted with diethyl ether, toluene and ethyl acetate. The solutions of organic solutes

ning agent was combined, dried and concentrated. The solid was purified by crystallization from toluene and the melting point was 145-146°C.

B. Preparation of α,α-bis(α-chlorophenyl)imidazole-2-methanol.

Using the method described in example VIC, but using an equivalent amount of α,α-bis(p_-chloro-phenyl)-l-(methoxymethyl)imidazole-2-methanol instead of the used 1- ( (benzyloxy)methyl]-α-(p_-chlorophenyl)-α-phenylimidazole-2-methanol gave a,α-bis(p_-chlorophenyl)-imidazole-2-methanol The melting point of the product was 195-197°C .

EXAMPLE VIII

A. Preparation of α-(p-fluorophenyl)-1-(methoxymethyl)-α-phenylimidazole-2-methanol.

Using the method described in Example VHA, but using an equivalent amount of 4-fluorobenzophenone instead of 4»4'-dichlorobenzophenone, a-(p_-fluorophenyl)-l-(methoxymethyl) was obtained -α-phenylimidazole-2-methanol. The melting point was 149.5-150.5°C after crystallization from acetone.

B. Preparation of α-(p_-fluorophenyl)-α-phenylimidazole-2-methanol.

Using the procedure described in Example VIC, but using an equivalent amount of α-(p-fluorophenyl)-1-(methoxymethyl)-α-phenylimidazole-2-methanol in place of the 1-[(benzyloxy)methyl)-α-(p-chlorophenyl)-α-phenylimidazole-2-methanol, α-(β-fluorophenyl)-α-phenyl-imidazole-2-methanol was obtained. The melting point was 199-200.5°C after crystallization from acetone.

EXAMPLE IX

A. Preparation of α,α-bis(α-bromophenyl)-1-(toluene-α-sulfonyl)-imidazole-2-methanol.

Using the procedure described in Example IA, but using an equivalent amount of 4>4'-dibromobenzophenone, dissolved in a 6:1:1 mixture of anhydrous tetrahydrofuran:benzene:diethyl ether in place of the 4-bromobenzophenone used α,α-bis(α-bromophenyl)-1-(toluene-α-sulfonyl)imidazole-2-methanol was obtained. The melting point was 144-146°C after crystallization from isopropyl alcohol.

Some unreacted ketone can be recovered by adding diethyl ether to the residue.

B. Preparation of α,α-bis(β-bromophenyl)imidazole-2-methanol.

Using the method described in Example IB, but using an equivalent amount of α,α-bis(β-bromophenyl)-1-(toluene-β-sulfonyl)imidazole-2-methanol instead of the used α-(p_-bromophenyl)-α-phenyl-1-(toluene-p_-sulfonyl)imidazole-2-methanol, α,α-bis(p_bromophenyl)imidazole-2-methanol was obtained. The melting point was 192-194°C after crystallization from isopropyl alcohol.

EXAMPLE X

A. Preparation of α-(o-chlorophenyl)-α-phenyl-1-(toluene-p-sulfonyl)-imidazole-2-methanol.

Using the procedure described in Example IA, but using an equivalent amount of 2-chlorobenzophenone ("J. Amer. Chem. Soc", 55, 534, (<1>944)) instead of 4-bromobenzophenone α-(o-chlorophenyl)-α-phenyl-1-(toluene-p_sulfonyl)imidazole-2-methanol was obtained. The melting point was 155-157°C after crystallization from toluene.

B. Preparation of α-(o-chlorophenyl)-α-phenylimidazole-2-methanol.

Using the method described in Example IB, but using an equivalent amount of a-(o-chlorophenyl)-a-phenyl-1-(toluene-£-sulfonyl)imidazole-2-methanol instead of a- (£-bromo-phenyl)-α-phenyl-1-(toluene-£-sulfonyl)imidazole-2-methanol, α-(o-chlorophenyl)-α-phenylimidazole-2-methanol was obtained. The melting point was 185-188°C after crystallization from isopropyl alcohol.

EXAMPLE XI

A. Preparation of α-(α-chlorophenyl)-α-phenyl-1-(toluene-α-sulfonyl)-imidazole-2-methanol.

Using the method described in Example IA, but by using an equivalent amount of 4-chlorobenzophenone instead of 4-bromobenzophenone, α-(£-chlorophenyl)-α-phenyl-1-(toluene-£- sulfonyl)imidazole-2-methanol. The melting point was 115-118°C after crystallization from a mixture of diethyl ether and petroleum ether (boiling range 28-40°C).

B. Preparation of α-(p-chlorophenyl)-α-phenylimidazole-2-methanol.

Using the method described in Example IB, but using an equivalent amount of α-(£-chlorophenyl)-α-phenyl-1-(toluene-£-sulfonyl)imidazole-2-methanol instead of α- (£-bromo-phenyl)-α-phenyl-1-{toluene-p__-sulfonyl)imidazole-2-methanol, α-(£-chlorophenyl)-α-phenylimidazole-2-methanol was obtained. The melting point was 163-165°C.

EXAMPLE XII

Preparation of α-(m-chlorophenyl)-α-phenylimidazole-2-methanol as hydrogen maleate.

When using the procedure described in the example

V, but by using an equivalent amount of l-bromo-3-chlorobenzene instead of l-bromo-4-chlorobenzene, a-(m-chlorophenyl)-a-phenyl-imidazole-2-methanol was obtained and this was purified by crystallization from a mixture of toluene and petroleum ether (boiling range 28-40°C). The melting point was 174-175°C.

The compound was converted to the maleate by dissoln

it in diethyl ether and add it to a solution of maleic acid in the same solvent. The salt was crystallized twice from a mixture of isopropyl alcohol and diethyl ether and then from a mixture of acetone and diethyl ether. The melting point was 151-153°C«

EXAMPLE XIII

Preparation of α,α-bis(α-chlorophenyl)-4,5-dimethyl-1-(1-propenyl)-imidazole-2-methanol.

Within an hour /\. 0 ml or 0.085 mol of it

20 percent butyllithium solution in n-hexane added dropwise with stirring under a nitrogen atmosphere at -60°C to a solution of 10.4 g or 0.0765 mol of l-allyl-4,5-dimethylimidazole and 9.3 g or 0.080 mol of N,N,N',N'-tetramethylethylenediamine in 125 ml of anhydrous tetrahydrofuran. Stirring was continued for a further two hours at -60°C and then 19.5 g or 0.078 mol of 4>4'-dichlorobenzophenone in 100 ml of anhydrous tetrahydrofuran was added dropwise. The reaction mixture was left overnight at room temperature and then 15 ml of water and a few pieces of solid carbon dioxide were added. The mixture was filtered and the filtrate was concentrated. The residue was extracted with a mixture of diethyl ether and 2N hydrochloric acid. The aqueous phase was made alkaline with potassium carbonate and extracted with diethyl ether. The extract was dried over sodium sulfate and concentrated. The residue was extracted again with 2N hydrochloric acid and diethyl ether and the aqueous phase was made alkaline again with potassium carbonate. The solid formed was filtered off and dissolved in boiling petroleum ether (boiling range 60-80°C). The undissolved substance was filtered off and the petroleum ether was distilled off. The residue was taken up in a very small amount of diethyl ether. The solution was cooled in a mixture of carbon dioxide and acetone and the precipitate was filtered off. α,α-bis(p-chlorophenyl)-4,5-dimethyl-1-(1-propenyl)imidazole-2-methanol was obtained. The melting point was 127-128°C.

EXAMPLE XIV

A. Preparation of α,α-bis(β-fluorophenyl)-1-(methoxymethyl)imidazole-2-methanol.

When using the method according to example VHA, however

by using 4>4'-difluorobenzophenone instead of 4>4'-dichlorobenzophenone, α,α-bis(p_-fluorenyl)-1-(methoxymethyl)imidazole-2-methanol was obtained. The melting point was 133°C•

B. Preparation of α,α-bis(p-fluorophenyl)imidazole-2-methanol.

Using the method described in example VIC, - but using an equivalent amount of α,α-bis(p_-fluorophenyl)-1-(methoxymethyl)imidazole-2-methanol instead of the used 1-( {benzyl-oxy)-methyl]-α-(p_-chlorophenyl)-α-phenylimidazole-2-methanol, α,α-bis(p_-fluorophenyl)imidazole-2-methanol was obtained. The melting point was 10/8-200°C.

EXAMPLE XV

Preparation of α,α-bis(p-trifluoromethyl-phenyl)-imidazole-2-methanol hydrochloride.

To a solution of 2.8 g or 0.025 ml 1-(methoxymethyl)imidazole and 3.5 g or 0.03 mo1 N,N,N',N'-tetramethylethylenediamine 1 50 ml anhydrous tetrahydrofuran was added a butyl lithium solution which was prepared from 0.5 g or 0.075 g atoms of lithium and 4.1 g or 0.030 mol of butyl bromide in 40 ml of anhydrous diethyl ether dropwise with stirring at a temperature of -60°C under a nitrogen atmosphere. After 2 hours, 8 g or 0.025 mol of 4,4'-bis(trifluoromethyl)benzophenone in

60 ml anhydrous tetrahydrofuran added at -60°C. The resolution was

sat overnight at room temperature and then it was decomposed

with 50 ml of water and extracted with diethyl ether. The extract was dried over sodium sulfate and the solvent was distilled off. The benzo- "'■ phenone precursor present in the residue was dissolved by boiling with petroleum ether (boiling range 4-0-60°C) and removed. The residue was then dissolved in a mixture of 75 ml of acetic acid, 7»5 m^- water and 75 ml of concentrated hydrochloric acid and the solution was refluxed for 5 hours The liquid was distilled off and the residue was extracted with a

mixture of 2N hydrochloric acid and diethyl ether. The ethereal layer was dried over sodium sulfate. The sodium sulfate was washed with acetone. The solutions in ether and acetone were combined and the solvents

was distilled from. The residue was washed with diethyl ether and filtered under suction. α,α-bis(α-tr±ELuormethyl-phenyl)imidazole-2-methanol hydrochloride was obtained. The melting point was 210-216°C during decomposition.

EXAMPLE XVI

A. Preparation of l-(met doxymethyl)-α-phenyl l-α-(m-trifluoromethyl J-phenyl)-

imidazole-2-methanol.

Under a nitrogen atmosphere and at a temperature between

-60° and -65°C was a butyl lithium solution, prepared from 2.04 g or 0.29 g atoms of lithium and 15-»8 g or 0.116 mol of butyl bromide in 130 ml of anhydrous. diethyl ether added dropwise to a solution of 9.8 g or 0.088 mol of 1-(methoxymethyl)imidazole and 10.2 g or 0.088 mol of N,N,N<J>,N'-tetramethylethylenediamine in 25O ml of anhydrous tetrahydrofuran. After 2

hour's stirring, a solution of 22 g or 0.088 mol of 3-(trifluoromethyl)benzophenone in 150 ml of anhydrous tetrahydrofuran was added dropwise

to the reaction mixture at a temperature of between -60° and -65°C. The reaction mixture was stirred for one hour at -65°C and then left overnight at room temperature. Then 20 ml of water was added to the reaction mixture and the solvents were distilled off. The residue was dissolved in dilute hydrochloric acid and the solution was washed with diethyl ether and made alkaline with potassium carbonate. The solid formed was filtered off and dissolved in chloroform. The solution was dried over sodium sulfate and the solvent was distilled off, after which the residue was crystallized from isopropyl alcohol. It was achieved. 1-(Methoxyethyl)-α-phenyl-α-(m-trifluoromethyl-phenyl)imidazole-2-methanol with a melting point of 152.5-153.5°C.

.1

B. Preparation of α-phenyl-α-(m-trifluoromethyl-phenyl)-imidazole-2-methanol.

A mixture of 13 g or 0.037 mol of 1-methoxymethyl-α-phenyl-α-(m-trifluoromethyl-phenyl)imidazole-2-methanol, 100 mt of glacial acetic acid,

10 ml of concentrated hydrochloric acid and 10 ml of water were refluxed for three hours. After cooling, the liquid was distilled off and the residue was dissolved in a small amount of ethanol. The solution was made alkaline with 2N sodium hydroxide solution and the alcohol was evaporated. The remaining aqueous phase was then extracted with diethyl ether. The extract was dried over sodium sulfate and the ether was distilled off. The residue was crystallized from toluene, the toluene solution was decolorized with activated charcoal. α-Phenyl-α-(m-trifluoromethyl-phenyl)-imidazole-2-methanol with a melting point of 151.5-152 >5°C was obtained.

EXAMPLE XVII

A. Preparation of 1-(Methoxyethyl)-α-phenyl-α-(β-trifluoromethyl-phenyl)-imidazole-2-methanol.

A butyl lithium solution, prepared from 1.02 g or 0.145 g atoms of lithium and 7 x 3 g or 0.058 mol of butyl bromide in 70 ml of anhydrous diethyl ether was added dropwise at -60° to -65°C under a nitrogen atmosphere to a solution of 4.9 g or 0.044 ml of 1-(methoxymethyl)imidazole and 5>1 g or 0.044-Wol N,N.,N',N'-tetramethylethylenediamine in 125 ml of anhydrous tetrahydrofuran. The reaction mixture was left for another 2 hours at -60°. -65°C and then 11 g or 0.044 ml of 4-(trifluoromethyl)benzophenone, dissolved in 75 ml of anhydrous tetrahydrofuran, was added dropwise. The temperature was maintained at -65°C for one hour and then the reaction mixture was allowed to reach room temperature overnight. 10 ml of water and solid carbon dioxide were added and the solvent was distilled off. The residue was dissolved in dilute hydrochloric acid and the solution was washed with diethyl ether and made alkaline with potassium carbonate. The resulting substance was filtered off and dissolved in chloroform. The solution was washed with water, dried over sodium sulfate and concentrated by evaporation of the solvent. The residue was crystallized from isopropyl alcohol. It was obtained l-(methoxymethyl)-α-phenyl-α—

(p_-trifluoromethyl-phenyl)imidazole-2-methanol. with a melting point of 158-159°c

B. Preparation of α-phenyl-α-(α-trifluoromethyl-phenyl)imidazole-2-methanol.

A mixture of 9 g or 0.025 ml of 1-(methoxymethyl)-α-phenyl-α-(£-trifluoromethyl-phenyl)imidazole-2-methanol, 10 ml of glacial acetic acid, 7 ml of concentrated hydrochloric acid and 7 ml of water was refluxed for 3>5 hours. After cooling, the liquid was distilled from 2N sodium hydroxide solution and a small amount of ethanol was added to the residue. The alcohol was distilled off and the aqueous phase was extracted with diethyl ether. The ethereal solution was washed with water and dried over sodium sulfate after which the solvent was distilled off. The residue was first crystallized from a mixture of toluene and petroleum ether (boiling range 4-0-60°C) and then from isopropyl alcohol.

α-Phenyl-α-(α-trifluoromethyl-phenyl)imidazole-2-methanol with a melting point of 174-175.5°C was obtained.

EXAMPLE XVIII

Preparation of α,α-bis(α-chlorophenyl)-1-methoxymethyl-imidazole-2-methanol.

To a solution of 22.4 g or 0.2 mol of 1-(methoxymethyl)imidazole in 150 ml of anhydrous tetrahydrofuran, 92 ml or 0.2 mol of butyllithium solution (20% in hexane) was added dropwise with stirring under a nitrogen atmosphere at -60°C. The reaction mixture was stirred for 2 hours after which anhydrous carbon dioxide gas was introduced. After stirring for one hour, the mixture was poured onto solid carbon dioxide. The lithium salt of 1-(methoxymethyl)imidazole-2-carboxylic acid precipitated. The salt was filtered off and washed with diethyl ether.

To a suspension of 16.2 g or 0.1 mol of the lithium salt and 35 g or 0.35 mol of triethylamine in 150 ml of anhydrous dichloromethane, 48>8 g or 0.45 mol of chlorocrimethylsilane were added dropwise with stirring under a nitrogen atmosphere. The mixture was stirred for 20 hours and then JQ0 ml of anhydrous toluene was added and stirring was continued for another hour. The lithium salts that formed were filtered off and the filtrate was concentrated by evaporation of the solvents. The residue containing the trimethylsilyl ester of 1-(methoxymethyl)xoidazole-2-carboxylic acid was dissolved in 100 ml of water-tetrahydrofuran and added dropwise to a refluxing solution of a Grignard compound prepared from 8.1 g or 093 g.atoms of magnesium and 57»5 g or 0.3 mo3 of 4-bromo-l-chlorobenzene: in 150 ml of anhydrous tetrahydrofuran. The mixture was refluxed for one hour and then decomposed in an ammonium chloride solution. The precipitate was filtered off and the filtrate was extracted with diethyl ether. The ethereal phase was extracted with 2N hydrochloric acid and the acidic extract was made alkaline with ammonia and extracted with diethyl ether. The ethereal extract was dried over sodium sulfate and the solvent was distilled off. The residue was crystallized twice from isopropyl alcohol and the was obtained α,α-bis(p_-chlorophenyl)-1-(methoxymethyl)imidazole-2-methanol with a melting point of 145-14-6°C.

The compound was converted to α,α-bis(p-chlorophenyl)imidazole-2-methanol as described in Example VIIB.

EXAMPLE XIX

A. Preparation of the ethyl ester of 1-(methoxymethyl)imidazole-2-carboxylic acid.

At a temperature of -10°C, 27.5 g or 0.25 m°l of ethyl chloroformate was added dropwise to a solution of 28 g or 0.25 mol of 1-(methoxyethyl)imidazole and 25 g or 0.25 m°l triethylamine in 125 ml anhydrous chloroform. The mixture was stirred at 0°C and then left for two days at room temperature. The precipitated triethylamine hydrochloride was filtered off and washed with diethyl ether. The filtrate was concentrated by evaporation of the solvents and the residue was dissolved in diethyl ether. The solution was dried over sodium sulfate, the ether was distilled off and the residue was distilled. The ethyl ester of 1-(methoxymethyl)imidazole-2-carboxylic acid with a boiling point of 120-124°C at 2 mm Hg was obtained.

B. Preparation of α,α-bis(α-chlorophenyl)-1-(methoxymethyl)imidazole-2-methanol.

The product was dissolved in 50 ml of anhydrous tetrahydrofuran

and added dropwise to a refluxing boiling solution of a Grignard compound prepared from 4.05 g or 0.15 g atoms of magnesium and 28.7 g or 0.15 mole of 4-bromo-1-chlorobenzene in 80 ml anhydrous tetrahydrofuran. The mixture was refluxed for one hour and then decomposed in an ammonium chloride solution. The precipitate was filtered off and the filtrate was extracted with diethyl ether. The ethereal phase was extracted with 2N hydrochloric acid and the acidic extract was made alkaline with ammonia and extracted with diethyl ether. The ethereal

extract was dried over sodium sulfate and the solvent was distilled off. The residue was crystallized twice from isopropyl alcohol. α,α-bis(β-chlorophenyl)-1-(methoxymethyl)imidazole-2-methanol with a melting point of 145-146°C was obtained.

EXAMPLE XX

A. Preparation of 1-(methoxymethyl)-4,5-dimethyl-imidazole.

At a temperature of 60°C, 500 mg of picric acid and 15.6 g or 0.39 ml of sodium hydroxide were added to a solution of 31 g or 0.32 mol of 4>5-dimethyl-imiciazole (H. Bredereck and G. Theilig, "Chem. Ber.", 86, 88 (1953)) in 150 ml of acetonitrile. Then 29 g or 0.36 mol of chloromethoxymethane was added dropwise, causing the temperature to rise to 80°C. The reaction mixture was refluxed for 6 hours and filtered. The filtrate was concentrated by distilling off the solvent and the residue was distilled. 1-(Methoxymethyl)-4,5-dimethylimidazole was obtained. The boiling point was 80-100°C at 1.0 mm Hg and the melting point of the hydrogen oxalate was 102-103°C.

B. Preparation of α,α-bis(α-chlorophenyl)-1-(methoxymethyl)-4,5-dimethylimidazole-2-methanol.

At a temperature of -60°C and under a nitrogen atmosphere, 114 ml or 0.24 ml of butyllithium solution (20% in hexane) was added dropwise with stirring to a solution of 28 g or 0.20 mol of l-(methoxymethyl )-4,5-dimethylimidazole and 28 g or 0.24 ml of N,N,N',N'-tetramethylethylenediamine in 200 ml of anhydrous tetrahydrofuran. After stirring for 2 hours, 50 g or 0.20 mol of 4>4'-dichlorobenzophenone in 250 ml of anhydrous tetrahydrofuran was added dropwise at -60°C. After standing overnight, the reaction mixture was extracted with water and the organic phase was concentrated by distilling off the solvents. The residue was treated with 2N hydrochloric acid and diethyl ether, resulting in the formation of an organic and an aqueous layer with an oily intermediate layer. The aqueous and oily layer was made alkaline with ammonia and extracted with diethyl ether. The extract was dried over sodium sulfate and the solvent was distilled off.

The oily residue was recrystallized three times from isopropyl alcohol and cx,α-bis(p_-chlorophenyl)-1-(methoxymethyl)-4,5-dimethylimidazole-2-methanol with a melting point of 151°C was obtained.

EXAMPLE XXI

A. Preparation of α-(o-tert.-butylphenyl)-α-ienyl-1-vinylimidazole-2-methanol.

To a solution of 28.6 g or 0.25 ml of N,N,N<f>,N<f->tetramethylethylenediamine and 17.6 g or 0.19 mol of 1-vinylimidazole in 300 ml of anhydrous tetrahydrofuran was dropwise with stirring added 14 ml or 0.25 m°l of 20 percent butyl lithium in n-hexane at -60°C under a nitrogen atmosphere during one hour. Stirring was continued for 2 hours under the same conditions, after which a solution of 48 g or 0.20 mol of 2-tert-butylbenzophenone in 300 ml of anhydrous tetrahydrofuran was added dropwise. The reaction mixture was stirred for 3.5 hours after which the cooling aids were removed and stirring was continued overnight under a nitrogen atmosphere. The lithium complex obtained was then decomposed with 15 ml of water and a large excess of solid carbon dioxide. The precipitate was filtered off, the filtrate was dried over sodium sulfate and the solvent was distilled off. The solid residue was crystallized twice from ethyl acetate to which a small amount of ethanol had been added. α-(_o-tert-butylphenyl)-α-phenyl-1-vinylimidazole-2-methanol with a melting point of 152-153°C was obtained.

B. Preparation of α-(o-tert-butylphenyl)-α-phenyl-imidazole-2-methanol.

To a solution of 10.0 g or 0.03 mol of "■-(o-tert.-butylphenyl)-a-phenyl-1-vinylimidazole-2-methanol in 180 ml of pyridine and 180 ml of 0.5N methanolic sodium hydroxide was added 360 ml of a 4 percent aqueous potassium permanganate solution dropwise at 20 to

30°C. After the addition was complete, 4>8 g of solid potassium permanganate were added (total permanganate 0.12 mol). The manganese dioxide was filtered off. The filtrate was treated with activated carbon, concentrated so to speak to dryness and poured into water. The solid was filtered off, dissolved in hot acetone, decolorized with activated charcoal and precipitated by addition of water. The precipitate was recrystallized from a mixture of acetone and water and a-(o-tert-butylphenyl)-a-phenylimidazole-2-methanoic with a melting point of 185-186°C was obtained.

EXAMPLE XXII

A. Preparation of α-(p-tert-butylphenyl)-α-phenyl-1-vinylimidazole-2-methanol.

This compound was prepared by the method described in Example XXI A using the following substances:

28.8 g (0.25 mol) N,N,N',N*-tetramethylethylenediamine,

17 >_6 g (0.19 mol) 1-vinylimidazole,

114 ml (0.25 mol) 20$ butyllithium in n-hexane,

48 g (0.20 mol) of p-tert-butylbenzophenone.

The product was crystallized twice from a mixture of ethyl acetate and petroleum ether (boiling range 28-40°C). Melting point 145-147°c«

B. Preparation of α-(p-tert-butylphenyl)-α-phenyl-imidazole-r2-methanol.

This compound was prepared by the method described in Example XXI B using 22.6 g or 0.068 mol of q-(p-tert-butylphenyl)-a-phenyl-1-vinylimidazoI-2-methanol, 820 ml 4 percent aqueous potassium permanganate and 11 g solid potassium permanganate (total permanganate 0.214 mol).- After the manganese dioxide had been filtered off, the excess of potassium permanganate in the filtrate was reduced to manganese dioxide by addition of sodium bisulphite. The precipitate was filtered off and the organic solvents were distilled off. The remainder of the filtrate was poured into water and the oil thus obtained was dissolved in diethyl ether. The solution was washed four times with water and dried over sodium sulfate and the solvent was distilled off. The resulting oil was taken up in as little acetone as possible and brought to crystallisation by the addition of petroleum ether (boiling range 28-40°C). Melting point l66-l68°C.

EXAMPLE XXIII.

A. Preparation of α,α-bis(p-tert..-butylphenyl)-1-vinylimidazole-2-methanol in

This compound was prepared by the method indicated in example XXII A using the following substances:

10g or 0.03 mo1 4,4*-di-tert.-butylbenzophenone,

19.5 ml or O.P^j. mol 20 percent butyllithium in n-hexane,

3 g or 0.03 ml of 1-vinylimidazole and

4.9 g or 0.04 mol of N,N,N',N'-tetramethylethylenediamine.

The product was crystallized from ethyl acetate. Melting point 169-170°C.

B. Preparation of α,α-bis(p-tert-butylphenyl)imidazoi-2-methanol. .... ', This" compound was prepared by the procedure indicated in Example XXII B using 8 g or 0.02 mol of a,a-bis(p_-tert,.-but<y>lfen< y>l)-l-vin<y>limidazole-2-methanol, 250 ml of 4 per cent potassium permanganate solution and 3.3 g of solid potassium permanganate (total permanganate 0.008 mol). After removing the manganese dioxide and the excess of permanganate, the organic solvents became distilled off and the remaining liquid was poured into water. A precipitate formed and this was filtered off and crystallized from a mixture of . C.

EXAMPLE XXIV

Preparation-of α,α-bis(α-fluorophenyl)-1-(methoxymethyl)-imidazole-2-methanol.

To a solution of 11.2 g or 0.1 mol of 1-(methoxymethyl)imidazole and 13.9 g or 0.12 mol of N,N,N',N'-tetramethylethylenediamine in 150 ml of anhydrous tetrahydrofuran 51 ml or 0.12 mol of a butyllithium solution (20% in n-hexane) was added dropwise over the course of one hour at -60°C and under a nitrogen atmosphere.' After the addition was complete, stirring was continued for a further 2 hours." The cooling aids were then removed and 25.1 g or 0.1 mol of 4,4'-difluorobenzophenone in 150 ml of anhydrous tetrahydrofuran was added dropwise. The reaction mixture was stirred for 6 hours. at room temperature and

it was then decomposed, with 15 ml of water. The precipitated lithium hydroxide was filtered off and the filtrate was concentrated by distilling off the solvents. 2N hydrochloric acid was added to the residue after which the mixture was extracted with diethyl ether. The aqueous phase was made alkaline with 2N sodium hydroxide solution. It formed

precipitate was filtered off, washed with water and crystallized twice from a mixture of isopropyl alcohol and petroleum ether (boiling range 40-60°C). α,α-bis(β-fluorophenyl)-1-(methoxymethyl)imidazole-2-methanol with a melting point of 133°C was obtained.

EXAMPLE XXV

A. Preparation of 4,5-diisobutyl-1-(methoxymethyl)imidazole hydrogen oxalate.

At a temperature of 60°C, 500 mg of picric acid and 22 g

or 0.55 ml of sodium hydroxide added to a suspension of 83 g or 0.46 mol of 4>5-diisobutyl-imidazole (H. Bredereck and G. Theilig, "Chem. Ber.", 85, 88 (1953)) in 600 ml of acetonitrile. Then 41 g or

0.51 mol of chloromethoxymethane was added dropwise with stirring, causing the temperature to rise to 80°C. The reaction mixture was refluxed for 2 hours and then shaken with water and diethyl ether. The ethereal phase was dried over sodium sulfate and the solvent was distilled off. An ethereal solution of oxalic acid was added to the residue, the precipitate was filtered off and crystallized four times from isopropyl alcohol. The melting point was 135-137°C

B. Preparation of α,α-bis(p-chlorophenyl)-4,5-diisobutyl-imidazole-2-methanol hydrogen maleate.

Under a nitrogen atmosphere and at -60°C, a butyl lithium solution prepared from 1.0 g or 0.15 g atoms of lithium and 8.2 g or 0.06 mol of butyl bromide in 50 ml of anhydrous diethyl ether was added dropwise with stirring to a solution of 11.2 g or 0.05 g of 1-4,5-diisobutyl-1-(methoxymethyl)imidazole and 7.0 g or 0.06 mol of N,N,N',N'-tetramethylethylenediamine in 100 ml anhydrous tetrahydrofuran. The mixture was stirred for 2 hours after which 12.5 S or 0.05 ml of 4>4f<->dichlorobenzophenone in 100 ml of anhydrous tetrahydrofuran was added dropwise.-^ The reaction mixture was left overnight and it was then completely

on ice and extracted with diethyl ether. The extract was dried over sodium sulfate and the solvent was distilled off. The rest crystallized

triturated three times from petroleum ether (boiling range 60-80°C).

A solution of 5.0 g of the obtained substance in 100 ml of glacial acetic acid, 10 ml of concentrated hydrochloric acid and 100 ml of water was refluxed for 5 hours. The liquid components were distilled off and ethyl alcohol was added to the residue until clear. resolution. The solution was then made alkaline with ammonia and extracted with diethyl ether. The extract was dried over sodium sulfate and the solvent was distilled off. The residue was dissolved in diethyl

ether and the solution was extracted with 2N hydrochloric acid. The extract

was made alkaline with ammonia and extracted with diethyl ether. The ethereal solution was dried over sodium sulfate and the ether was distilled off. To the residue was added an ethereal solution of maleic acid. The precipitate was filtered off and crystallized three times from isopropyl alcohol and a,a-bis(£-chlorophenyl)-4,5-diisobutylimidazole-2-methanol hydrogen maleate with a melting point of 188-189°C was obtained.

EXAMPLE XXVI

Preparation of α-(o-tert-butylphenyl)-1-(methoxymethyl)-α-phenyl-2-imidazole-2-methanol.

Under a nitrogen atmosphere and at -60°C, 38 ml or 0.08 mol of a butyllithium solution (20% in n-hexane) was added dropwise over the course of one hour to a mixture of 9>6 g or 0.08 mol of N ,N,N',N'-tetramethylethylenediamine and 7 g or 0.06 mol of 1-(methoxymethyl)imidazole in 100 ml of anhydrous tetrahydrofuran. The mixture was stirred for a further 2 hours under the same conditions after which 16 g or 0.0675 ml of o-tert-butylbenzophenone in 100 ml of anhydrous tetrahydrofuran was added dropwise. After the addition was complete, the mixture was stirred for 2 hours at -60°C and one hour at room temperature. The mixture was decomposed with 5 ml of water, the precipitate was filtered off and the filtrate was dried over sodium sulfate and concentrated. The solid residue was crystallized from isopropyl alcohol and α-(o-tert-butylphenyl)-1-(methoxymethyl)-α-phenyl-2-imidazole-2-methanol with a melting point of L49-150°C was obtained.

EXAMPLE XXVII

A. Preparation of 1-allyl-4(or 5)-(p-chlorophenyl)imidazole.

A mixture of 53.6 g or 0.3 mol of 4(5)-(£-chlorophenyl)-imidazole, 14.4 g or 0.36 mol of sodium hydroxide, 100 mg of picric acid and 150 ml of acetonitrile was heated to 60°C under stirring. Then 25.3 g or 0.33 mol of freshly distilled allyl chloride was added dropwise. The mixture was refluxed for 5 hours and filtered. The filtrate was concentrated and water and diethyl ether were added to the residue. The ether phase was washed with water, dried over sodium sulfate and concentrated. The rest was distilled. 1-allyl-4(or 5)-(£-chlorophenyl)imidazole with a boiling point of 157-170°C at 0.5-1.0 mm Hg was obtained.

B. Preparation of α,α,4(or 5)-tris(α-chlorophenyl)-1-(1-propenyl)-imidazole-2-methanol.

Over half an hour, 89 mL or 0.145 mo1 of 15$ butyllithium in n-hexane was added dropwise under a nitrogen atmosphere at -60° to -70°C to a solution of 28.4 g or 0.13 mo1 of 1-allyl- 4(or 5)-(£-chlorophenyl)imidazole and 16.8 g or 0.145 mol of N,N,N',N'-tetramethylethylenediamine in 150 ml of anhydrous tetrahydrofuran. The mixture was stirred for an additional 2 hours under the same conditions. Then a solution of 32>6 g or 0.13 mol of 4>4'-dichlorobenzophenone in 100 ml of anhydrous tetrahydrofuran was added dropwise and after the addition was complete the mixture was stirred for a further hour. The cooling aids were removed and the mixture was left overnight at room temperature under a nitrogen atmosphere. The reaction mixture was then decomposed by stirring for half an hour with 20 ml of water. The organic phase was separated off, washed with dilute hydrochloric acid until it was obviously acidic, washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was dissolved in a small amount of diethyl ether with some methanol added. By to-

addition of petroleum ether (boiling range 40-60°C) a solid precipitated which was filtered off and crystallized twice from isopropyl alcohol.

α,α,4(or 5)-tris(p-chlorophenyl)-1-(1-propenyl)-imidazole-2-methanol with melting point 137-139°^' was obtained

C. Preparation of α,α,4(5)-tris(α-chlorophenyl)imidazole-2-methanol.

At 0-5°C, 425 ml of a 4% aqueous potassium permanganate solution was added dropwise over the course of one hour to a solution of 16.7 g or 0.0356 mol a,a,4(or 5)- tris(£-chlorophenyl)-1-(1-propenyl)imidazole-2-methanol in a mixture of 220 ml of pyridine and 220 ml of 0.5N ethanolic sodium hydroxide. Then 4>4 g of potassium permanganate were added in small portions to the reaction mixture. The reaction mixture was left overnight at room temperature. The manganese dioxide formed was filtered off, the filtrate was decolored with sodium metabisulphite and activated charcoal and the solvent was distilled off under reduced pressure. The rest was suspended in water. The aqueous phase was extracted with diethyl ether, the extract was dried over sodium sulfate and concentrated. The residue was dissolved in as little boiling isopropyl alcohol as possible. Petroleum ether (boiling range 60-80°C) was added

set, causing a,a,4(5)-tris(£-chlorophenyl)imidazole-2-meta-

noi was dropped. The product was crystallized from a mixture of isopropyl alcohol and petroleum ether (boiling range 60-80°C). Melting point 184-185°C.

EXAMPLE XXVIII

A. Preparation of α,α-bis(2,4-dichlorophenyl)-1-(methoxymethyl)imidazole-2-methanol.

To a solution of 7.6 g or 0.0676 mol of (methoxymethyl)imidazole and 8.1 g or 0.0676 mol of N,N,N',N'-tetramethylethylenediamine in 150 ml of anhydrous tetrahydrofuran was added dropwise under a nitrogen atmosphere at -60°C added 43 ml or 0.070 mol n-butyl lithium solution (15 $ in n-hexane). The solution was stirred at -60°C for 1 hour. Then, 23 g or 0.0676 mol of 2,2',4,4'-tetrachloro-benzophenone (prepared as described by S.D. Wilson and Yuan Ying Cheng, "J. Org. Chem.", 5, 223-226 ( 1940)) in 150 ml anhydrous tetrahydrofuran added dropwise. The solution was stirred for an additional hour at -60°C and overnight at room temperature. The reaction mixture was decomposed with 100 ml of water and extracted with diethyl ether. The organic phase was dried over sodium sulfate and concentrated and the residue was extracted with a mixture of 2N hydrochloric acid and diethyl ether, after which a solid was formed which was crystallized from a mixture of isopropyl alcohol and diethyl ether. The product proved to be the hydrochloride of the desired compound, contaminated with the compound without the methoxymethyl group. Ammonia and diethyl ether were added to set the base free. The ethereal phase was concentrated and the residue was crystallized four times from a mixture of isopropyl alcohol and petroleum ether with a boiling range of 60-80°C. α,α-bis(2,4-dichlorophenyl)-1-(methoxymethyl)imidazole-2-methanol with a melting point of 145 > 5-14-6°C was obtained.

B. Preparation of α,α-bis(2,4-dichlorophenyl)imidazole-2-methanol.

A solution of 10 g or 0.023 mol of α,α-bis(2,4-dichloro-phenyl)-1-(methoxymethyl)imidazole-2-methanol in 150 ml of glacial acetic acid, 15 ml of concentrated hydrochloric acid and 15 ml of water was refluxed for 2 hours and then concentrated. The residue was dissolved in a small amount of a mixture of ethanol and 2N hydrochloric acid and the solution was extracted with diethyl ether. The extract was dried over sodium sulfate and the ether was distilled off. Diethyl ether and petroleum ether (boiling range 60-80°C) were added, the solid was filtered off and crystallized twice from. isopropyl alcohol with a small amount of ethanol. α,α-bis(2,4-dichlorophenyl)imidazole-2-methanol with a melting point of 193°C was obtained.

EXAMPLE XXIX

A. Preparation of α-(p_-tert-butylphenyl-α-(jD-chlorophenyl)-1-(methoxymethyl)imidazole-2-methanol.

This compound was prepared by the method described in Example XXVII B using the following substances:

11.2 g or 0.1 mol 1-(methoxymethyl)imidazole, 13»35 g or 0.115

mol N,N,N',N'-tetramethylethylenediamine in 250 ml anhydrous tetrahydrofuran, 70 ml or 0.115 mol 15% butyllithium in n-hexane, 27.3 g or 0.1 mol 4-tert.-butyl-4'- chlorobenzophenone (F.A. Vingiello and C.K. Bradsher,

"J. Am. Chem. Soc", Jl, 357<2> (1949)) in 150 ml of anhydrous tetrahydrofuran. After decomposition of the reaction mixture with 25 ml of water, the organic phase was separated off, washed three times with an aqueous sodium chloride solution and dried over sodium sulfate. The solvent was distilled off and the residue was suspended in a small amount of cold diethyl ether. The solid was filtered off and crystallized twice from acetone. α-(p-tert-butylphenyl)-α-(p-chloro-phenyl)-1-(methoxymethyl)imidazole-2-methanol with a melting point of ~"-—" lb2-163°C was obtained.

B. Preparation of α-(p-tert-butylphenyl)-α-(p-chlorophenyl)imidazole-2-methanol.

A mixture of 13 g or 0.034 mol of α-(p-tert-butylphenyl)-α-(p_-chlorophenyl)-1-(methoxymethyl)imidazole-2-methanol, 150 ml of glacial acetic acid, 15 ml of concentrated hydrochloric acid and 15 ml of water was boiled under reflux for 3 l/2 hours. The reaction mixture was treated with activated charcoal and concentrated. The residue was dissolved in diethyl ether and the solution was washed with water. An ether solution of oxalic acid was added to the ether phase. The precipitate thus formed was crystallized from ethanol with a small amount of methanol. The base was set free by addition of sodium hydroxide and extraction with diethyl ether. The ether was distilled off and the residue was crystallized from isopropyl alcohol. As the product obtained contained crystalline isopropyl alcohol, it was dissolved in diethyl ether. The ether phase was washed with water and dried over sodium sulfate and the ether was distilled off. α-(p-tert-butylphenyl)-α-(jD-chlorophenyl)imidazole-2-methanol was obtained. The melting point was 95-110°C. The melting point was not sharp, but NMR and IR spectra, titration and elemental analysis confirmed that the desired structure had been achieved. Thin-layer chromatography confirmed only one component.

EXAMPLE XXX

A. Preparation of α-(2,4-dichlorophenyl)-α-(p-fluorophenyl)-1-(methoxymethyl)imidazole-2-methanol.

At -60°C and under a nitrogen atmosphere, 44 ml or 0.072 mol of n-butyllithium (15% solution in n-hexane) was added dropwise with stirring to a solution of 7>8 g or 0.07 ml of 1-(methoxy -methyl) imidazole and 8.1 g or 0.072 mol of N,<N,N>',N'-tetramethylethylenediamine in 100 ml of anhydrous tetrahydrofuran. The mixture was stirred for one hour after which 18.9 g or 0.070 mol of 2,4-dichloro-4'-fluorobenzophenone in 100 ml of anhydrous tetrahydrofuran was added at -60°C. The solution was stirred for one hour at -60°C and left overnight at room temperature. Then ^0 ml of water was added and the solid formed was filtered off. The filtrate was extracted with tetrahydrofuran and diethyl ether. The organic phase was dried over sodium sulfate and the solvents were distilled off. Diethyl ether was added to the semi-solid residue and the solid was filtered off. This product was combined with the solid obtained after the addition of water. The substance was crystallized twice from acetone with a small amount of dimethylformamide and α-(2,4-dichlorophenyl)-α-(p_-fluorophenyl)-1-(methoxymethyl)imidazole-2-methanol was obtained with melting point 179°C.

B. Preparation of α-(2,4-dichlorophenyl)-oc-(α-fluorophenyl)imidazole-2-methanol.

A solution of 12 g or 0.031 mol of α-(2,4-dichloro-phenyl)-α-(£-fluorophenyl)-1-(methoxymethyl)imidazole-2-methanol, 150 ml of glacial acetic acid, 15 ml of concentrated hydrochloric acid and 15 ml of water was boiled under reflux for 5 hours. The dark brown solution was concentrated and water was added to the residue. The mixture was then made alkaline by the addition of ammonia and extracted with diethyl ether. The organic phase was separated off, decolorized with activated charcoal, dried over sodium sulfate and the ether was distilled off. The solid residue was crystallized twice from acetone, washed again with petroleum ether (boiling range 60-80°C) and crystallized once from isopropyl alcohol. cc-(2,4-Dichlorophenyl)-α-(13-fluorophenyl)imidazole-2-methanol with a melting point of 193.5-194°C was obtained.

EXAMPLE XXXI

A. Preparation of α-(2,4-dichlorophenyl)-1-(methoxymethyl)-α-phenyl-imidazole-2-methanol.

This compound was prepared in the manner described in Example XXVII B using the following substances: 9.8 g or 0.088 mol l-(methoxymethyl)imidazole, 10.4 g or 0.09 m°l N,N,N ',N'-tetramethylethylenediamine in 100 ml of anhydrous tetrahydrofuran, 62 ml or 0.10 mol of 15% butyllithium in n-hexane and 22.6. g or 0.09 mol of 2,4-dichlorobenzophenone in 100 ml of anhydrous tetrahydrofuran.

The reaction mixture was decomposed with 75 ml of water.

The solid that formed was filtered off and the aqueous phase

of the filtrate was discarded. The organic phase was concentrated. The residue turned out to be identical to the solid material that had been filtered off.

The combined solids were crystallized from isopropyl alcohol and α-(2,4-dichlorophenyl)-1-(methoxymethyl)-α-phenylimidazole-2-methanol with a melting point of 161-161.5°C was obtained.

B. Preparation of α-(2,4-dichlorophenyl)-α-phenylimidazole-2-methanol.

A mixture of 11 g or 0.033 mol of α-(2,4-dichlorophenyl)-1-(methoxymethyl)-α-imidazole-2-methanol, 90 ml of glacial acetic acid, 9 ml of water and 9 ml of concentrated hydrochloric acid was refluxed for 3 hours. The acetic acid was distilled off and the residue was dissolved in a mixture of water and ethanol. The solution was made alkaline with 2N aqueous sodium hydroxide, the alcohol was distilled off and the aqueous solution was filtered. The filtrate was extracted with diethyl ether and the extract was dried over sodium sulfate and concentrated. The residue and the solid filtered off were combined and crystallized from acetone with a small amount of ethanol. α-(2,4-Dichlorophenyl)-α-phenylimidazole-2-methanol with a melting point of 176-177°C was obtained.

EXAMPLE XXXII

Preparation of 1-allyl-α-(£-chlorophenyl)-α-phenylimidazole-2-methanol.

A mixture of 3>4 g or 0.028 mol fresh, distilled allyl bromide, 7 g or 0.025 ml α-.(£-chlorophenyl.)-α-phenylimidazole-2-methanol-(prepared according to Example IV), 1.2 g or 0.030.mol of sodium hydroxide, 0.050 g of picric acid and 50 ml of acetonitrile were refluxed for 5 hours. The hot reaction mixture was filtered and water was added to the filtrate. The precipitate formed was filtered off, washed with water and petroleum ether (boiling range 4-0-60°C) and crystallized three times from isopropyl alcohol. 1-allyl-α-(£-chlorophenyl)-α-phenylimidazole- 2-methanol with a melting point of 165-165.5°C•

EXAMPLE XXXIII

Preparation of α,α-bis(α-chlorophenyl)-1-vinylimidazole-2-methanol.

At a temperature of -60° to -70°C and under a nitrogen atmosphere, 25 ml or 0.04 mol of 15$ butyllithium in n-hexane was added to a solution of 3.>2 g or 0.034 mol of 1-vinylimidazole and 4, 6 g or 0.04 mol of N,N,N<f>,N'-tetramethylethylenediamine in 75 ml of anhydrous tetrahydrofuran. The mixture was stirred for 2 hours and. then 8.5 g or 0.034 mol of 4i4'-dichlorobenzophenone, dissolved in 75 ml of anhydrous tetrahydrofuran, was added dropwise under the same conditions. The reaction mixture was stirred for 2 hours at -60° to -7-0°C and left overnight at room temperature under a nitrogen atmosphere. Then 25 ml of water and a small amount of acetic acid were added to the reaction mixture and the liquid was distilled off. Water was added to the residue and the solid was filtered off. ' The product was crystallized from a. mixture of isopropyl alcohol, dimethylformamide and petroleum ether (boiling range 60-80°C). α,α-bis(α-chlorophenyl)-1-vinylimidazole-2-methanol was obtained with

a melting point of 173.5-<1>74°C.

EXAMPLE XXXIV

Preparation of α-phenyl-α-(α-trifluoromethylphenyl)-1-vinylimidazole-2-methanol.

This compound was prepared by the method described in Example XXXIII using the following substances: 8.5 g or 0.034 mol of £-trifluoromethylbenzophenone, 3.2 g or 0.034 mol of 1-vinylimidazole, 4>6 g or 0, 04 m°l N,N,N<T>,N'-tetramethylethylenediamine, 25 ml or 0.04 m°l 15 °/ ° butyllithium in n-hexane.

The compound was crystallized from a mixture of acetone and petroleum ether (boiling range 60-80°C). Melting point 173.5-174°C.

EXAMPLE XXXV

Preparation of 1-benzyl-oc-phenyl-α(p-trifluoromethylphenyl)imidazole-2-methanol.

A solution of 14.2 g or 0.09 ml of 1-benzylimidazole (A.M. Roe, "J. Chem. Soc", 1963, 2195) in 60 ml of tetrahydrofuran was added dropwise at -20° to -30°C under a nitrogen atmosphere to 0.1 mole of phenyllithium (prepared from 1.52 g or 0.22 g.atoms of lithium and 15.7 g or 0.19 m°l of bromobenzene) in " JO ml of diethyl ether. The reaction mixture was stirred for one hour and then 22.5 g or 0.09 mol of 4-(trifluoromethyl)-benzophenone in 35 ml of tetrahydrofuran was added dropwise.The reaction mixture was stirred under nitrogen atmosphere for two hours

at -20° to -30°C and for 15 hours at room temperature. The mixture was then poured into a mixture of ice and water. The aqueous phase was extracted twice with diethyl ether and the combined extracts were concentrated. The residue was taken up in diethyl ether and the undissolved solid (ketone starting material) was filtered off. The ether was distilled off and the residue was again taken up in a small amount of diethyl ether. The undissolved material which now proved to be the desired product was filtered off. This procedure (evaporating the ether and taking up the residue in ether again) was repeated a few times and the solids filtered off were combined. This was crystallized from isopropyl alcohol with a small amount of water and 1-benzyl-a-phenyl-a-(£-trifluoromethylphenyl)-imidazole-2-methanol with a melting point of 167-169°C was obtained.

EXAMPLE XXXVI

Preparation of 1-benzyl-α,α-bis(α-chlorophenyl)imidazole-2-methanol.

A solution of 17.4 g or 0.11 mol of N-benzylimidazole

in 40 ml of anhydrous tetrahydrofuran was added dropwise over one hour at -20° to -30°C under a nitrogen atmosphere to a phenyllithium solution prepared from 1.67 g or 0.24 g.atoms of lithium and 18.8 g or 0.12 mol of bromobenzene in 80 ml of anhydrous diethyl ether. The mixture was heated for about an hour until a bright red homogeneous solution was obtained. Then a solution of 25.1 g or 0.1 mol

4,4'-dichlorobenzophenone in 60 ml of anhydrous tetrahydrofuran added over the course of one hour at a temperature between -25° and -15°C. The reaction mixture was stirred for 15 hours at room temperature under a nitrogen atmosphere and then poured onto 200 g of ice. The aqueous phase was saturated with sodium chloride and the organic phase was separated off and concentrated. The residue was dissolved in a small amount of acetone and the solution was acidified with 2N hydrochloric acid. Then some toluene was added and the precipitate formed was filtered off. The product was crystallized three times from a mixture of isopropyl alcohol and petroleum ether (boiling range 28-40°C). 1-Benzyl-α,α-bis(p-chlorophenyl)imidazole-2-methanol with a melting point of 167-168°C was obtained.

EXAMPLE XXXVII

Preparation of 1-benzyl-α,α-bis(p_-fluorophenyl)imidazole-2-methanol.

By following the procedure set forth in Example XXXVI, but using an equivalent amount of 4>4'-difluorobenzophenone (J.P. Picard and C.W. Kearns, "Can. J. Research", 28 B, 56 (1950)) instead for 4>4'-dichlorobenzophenone a reaction mixture was obtained which was poured into a mixture of ice and sodium chloride. The organic phase was separated off, dried over sodium sulphate and the solvent was distilled off. - Diethyl ether was added to the residue and the insoluble substance, consisting of the desired compound, was filtered off. The product was crystallized from isopropyl alcohol and 1-benzyl-α,α-bis(p-fluorophenyl)imidazole-2-methanol with a melting point of 176-177°C was obtained.

EXAMPLE XXXVIII

Preparation of 1-benzyl-α-(o-chlorophenyl)-α-phenylimidazole-2-methanol.

The reaction procedure set forth in Example XXXVI was repeated with o-chlorobenzophenone in place of 4>4'-dichlorobenzophenone. The ketone was added at a temperature between 0° and 5°C. The mixture was stirred overnight at room temperature and then poured into 200 ml of ice. The aqueous phase was saturated with sodium chloride and the organic phase was separated off. The solvents were distilled off and diethyl ether was added to the residue. The undissolved substance was filtered off and crystallized three times from a mixture of chloroform and petroleum ether (boiling range 40-60°C). 1-Benzyl-α-(o-chlorophenyl)-α-phenyl-imidazole-2-methanol with a melting point of 167.5-168°C was obtained.

EXAMPLE XXXIX

Preparation of 1-benzyl-α-(p-chlorophenyl)-α-phenylimidazole-2-methanol.

The procedure of Example XXXVIII was repeated with p-chlorobenzophenone instead of o-chlorobenzophenone. The reaction mixture was poured onto ice and the organic phase was separated off and concentrated. The residue was dissolved in a small amount of acetone after which 2N hydrochloric acid was added to the solution. The mixture was extracted with diethyl ether and the remaining aqueous phase was extracted with chloroform. The chloroform extract was concentrated and the residue was shaken with 2N sodium hydroxide solution after which the desired compound crystallized out. The product was filtered off and crystallized twice from a mixture of acetone and petroleum ether (boiling range 28-40°C) and twice from ethanol. 1-Benzyl-α-(p_-chlorophenyl)-α-phenylimidazole-2-methanol with a melting point of 174-175°c was obtained

EXAMPLE XL.

Preparation of α-(β-chlorophenyl)-1-phenethyl-α-phenylimidazole-2-methanol.

A solution of 20 ml of 20% butyllithium in n-hexane (0.043 mol) in 30 ml of diethyl ether was added dropwise under a nitrogen atmosphere to a solution of 5.5 g or 0.032 mol of 1-phenethylimidazole ("J. Am. Chem . Soc", 21» 4000 (1949)) in 100 ml of diethyl ether. After the addition was complete, the reaction mixture was stirred for an additional hour at room temperature. Then a solution of 7.8 g or 0.036 mol of 4-chlorobenzophenone in 75 ml of anhydrous diethyl ether was added dropwise. The reaction mixture was stirred for 3 hours and then poured into 200 ml of ice water. The ether layer was separated, dried over sodium sulfate and the ether was distilled off. The residue was crystallized from a mixture of ethanol and petroleum ether (boiling range 40-60°C). α-(£-Chlorophenyl)-1-(phenethyl-α-phenylimidazole-2-methanol) with a melting point of 164-165°C was obtained.

EXAMPLE XLI

Preparation of α-(£-chlorophenyl)-1-methyl-α-phenylimidazole-2-methanol.

A solution of 25.5 g or 0.08 mol of 20% butyllithium in n-hexane in 50 ml of anhydrous diethyl ether was added at room temperature to a solution of 5 g or 0.06 mol of 1-methyl-imidazole in 50 ml of anhydrous diethyl ether . The reaction mixture was stirred for one hour and then

a solution of 15.6 g or 0.07 mol of -4-chlorobenzophenone in diethyl ether was added dropwise. The reaction mixture was stirred for 3 hours and then poured into in a mixture of ice and .water. The solid was filtered off and crystallized from ethanol. α-(£-Chlorophenyl)-1-methyl-α-phenyl-imidazole-2-methanol was obtained with a melting point of 185-186°C.

EXAMPLE XLII

A. "Preparation of l-(-p-chlorobenzyl).lmidazoloxalate (1:1)..

A mixture of 13-.6 g or 0.2 mol imidazole., -%. 6 g or 1.24 mol of sodium hydroxide and 150 ml of acetonitrile were stirred for one hour. Then 0.5 g of 50 percent picric acid in water and a few crystals of potassium iodide were added to the suspension. The homogeneous reaction mixture that was obtained was heated to 50°C and at this temperature a solution of 35.4 g or 0.22 mol of £-chlorobenzyl chloride in 50 ml of acetonitrile was added dropwise. The reaction mixture was then boiled under reflux for 4 hours. After cooling, the solid substance (sodium chloride) was filtered off. The solvent was evaporated and the residue was distilled. The boiling range of the main fraction was

.144-166°C at 0.6 .mm Hg..This product was dissolved in.anhydrous diethyl ether and an ether solution of .oxalic acid was added, causing the desired oxalate to .precipitate...The salt was crystallized from ethanol and had a melting point of .137>5-139»5°C"

VB. -Preparation ..of l-(;£-chlorobenzyl«)--a.,.a-bis(£-chlorophenyl)-imidazole—

.2-methanol.

.! over the course of one hour, 64 ml .or 0.105 mol of 15% butyllithium irn-hexane^was added dropwise at -65° to -70°C under a pure nitrogen atmosphere to ;a ...solution of . 1% 3 g or 0.1 mol of 1-(£-chlorobenzyl)-imidazole (prepared from the oxalate described under A) and 12.2 g

■ or .Q.,,105 mol iN^N^N'..,^'—tetramethylethylenedlamine in 150 ml anhydrous

.tetrahydrofuran. Reaks ion mixture Ale stirred for one -hour and then ible ien >susp.ens'joii .of -2 5-, A g .or '.A,! -mol ,4>, 4 '-dichlorobenzophenone 1.150 nnl -anhydrous tetrahydrofuran added -'rapidly under the same reaction conditions. Stirring was continued for one hour and then the cooling aids, the iron and the reaction mixture were left overnight at room temperature in 20 ml of water. was added and the organic phase was separated off and concentrated. The residue was suspended in a mixture

of water and diethyl ether. The solid formed was filtered off and the ether layer was separated off, dried over sodium sulfate and concentrated. The residue was crystallized twice from methanol and 1- (£-chlorobenzyl)-α,α-bis(p-chlorophenyl)imidazole-2-methanol with a melting point of 171-173°C was obtained.

EXAMPLE XLTII

Preparation of α,α-bis(α-chlorophenyl)-1-methylimidazole-2-methanol.

To a suspension of 9>6 g or 0.030 mol of a,a-bis(£-chlorophenyl)imidazole-2-methanol (prepared according to Example III) in 100 ml of acetonitrile was added 500 mg of picric acid, 300 mg of potassium iodide and 1.45 g or 0.036 mol of sodium hydroxide at 60°C. The reaction mixture was stirred for one hour and then 4.7 g or 0.033 ml of methyl iodide in 25 ml of acetonitrile was added dropwise at 55°C. The mixture was refluxed for 4 hours, the solvent was distilled off and the residue was extracted with a mixture of water and diethyl ether. The solid was filtered off and the ether phase was dried over sodium sulfate and concentrated. Diethyl ether was added to the residue and the solid was filtered off. The two portions of solid were combined and crystallized twice from isopropyl alcohol and twice from toluene and washed again with petroleum ether (boiling range 60-80°C). α,α-bis(α-chlorophenyl)-1-methylimidazole-2-methanol with a melting point of p,190-191°C was obtained.

EXAMPLE XLIV

Preparation of 1-(methoxymethyl)-α,α-bis(α-trifluoromethylphenyl)imidazole-2-methanol.

9.1 ml or 0.015 mol of n-butyllithium solution (15% in n-hexane) was added dropwise with stirring at -60°C and under a nitrogen atmosphere to a solution of 1.7 g or 0.015 mol of l-(methoxy-methyl) imidazole and 1.8 g or 0.015 mol of E>N,N',N<f>-tetramethylethylenediamine in 75 ml of anhydrous tetrahydrofuran. Stirring was continued for 1.5 hours/- and then 2.9 g or 0.0091 mol of 4,4f-bis(trifluoromethyl)benzophenone in ml of anhydrous tetrahydrofuran was added dropwise under the same conditions, resulting in a color change from light red to very dark red. The reaction mixture was left overnight at room temperature and it was then decomposed by adding 40 ml of water. The mixture was extracted with diethyl ether and the extract

-was concentrated; The residue was extracted with a mixture of 2N hydrochloric acid and diethyl ether. The ether phase was dried over sodium sulfate and the ether was distilled off... The residue was boiled a few times with petroleum ether (boiling range 40-60°C') to remove ketone starting material. and it was then crystallized once from a mixture of toluene and petroleum ether (boiling range 28-40°C) and twice from petroleum ether (boiling range

IOC-I4O C). 1-(Methoxymethyl)-α,α-bis(p-trifluoromethylphenyl)'imidazole-2-methanol with a melting point of 160-161°C was obtained.

EXAMPLE XLV

Preparation of 1-([benzyloxy)methyl]-α,α-bis(p-chlorophenyl)imidazole-2-methanol.

A mixture of 125 ml of acetonitrile, 9.2 g of α,α-bis(p-chlorophenyl)imidazole-2-methanol (prepared according to Example III) and 1.5 g of sodium hydroxide was stirred for one hour. To the now homogeneous reaction mixture, $ 00 mg of picric acid and some crystals of potassium iodide were added and the mixture was heated to ^ >0°C. A solution of 5>2 g of benzyloxymethyl chloride in 50 ml of acetonitrile was then added dropwise and the reaction mixture was then refluxed for 4 hours. The mixture was cooled and filtered and the filtrate was concentrated under reduced pressure. The residue was suspended in water and the suspension was extracted with diethyl ether. The extract was dried over sodium sulfate and the ether was distilled off. The solid residue obtained was recrystallized from isopropyl alcohol. The product was then boiled four times with 75 ml of petroleum ether (boiling range 60-80°C'), where the petroleum ether was decanted each time, after which the product was crystallized once into isopropyl alcohol. The substance obtained was

dried in vacuum for 10 hours at 110°C and 1-((benzyloxy)-'-methyl]-a,a-bis(£-chlorophenyl)imidazole-2-methanol with a melting point of

139-141°C.

EXAMPLE XLVI

Preparation of α,α-bis(α-chlorophenyl)-1-vinylimidazole-2-methanol.

2.19 g or 0.03 g atoms of magnesium and 10.9 g or 0.1 mole of ethyl bromide were converted to a Grignard compound in 50 ml of refluxing anhydrous tetrahydrofuran. During 5 minutes, a solution of 8.46 g or 0.09 mol of 1-vinylimidazole in

20 ml of anhydrous tetrahydrofuran added with stirring to the mixture after which the reaction mixture was refluxed for a further two hours. A suspension of 22.6 g or 0.09 ml of 4>4,_(iichlorobenzophenone in 5 ml of anhydrous tetrahydrofuran was then added and reflux continued for a further 24 hours. This was all done under a nitrogen atmosphere . After cooling, the reaction mixture was poured into a mixture of ice, water and ammonium chloride. The mixture was then extracted with diethyl ether and the extract was washed with water, dried over sodium sulfate and concentrated. The solid residue was crystallized twice from a mixture of isopropyl alcohol and dimethylformamide. α,α-bis(α-chlorophenyl)-1-vinylimidazole-2-methanol was obtained with a melting point of 173>5-174°C»

EXAMPLE XLVII

Preparation of 1-benzyl-α,α-bis(p-chlorophenyl)imidazole-2-methanol.

A solution of 19.2 g of α,α-bis(p-chlorophenyl)imidazole-2-methanol (prepared according to Example III B) and 3 g of sodium hydroxide in 250 ml of acetonitrile was refluxed for one hour with stirring. Then $ 00 mg of picric acid, some crystals of potassium iodide and a solution of 11.3 S benzyl bromide in 100 ml of acetonitrile were added. The reflux was then continued for 4 hours with stirring. The reaction mixture was left overnight. The precipitate formed was filtered off and dissolved in 3 liters of diethyl ether. This solution was washed with a saturated sodium chloride solution, decolorized with activated charcoal, dried over sodium sulfate and concentrated. The residue was crystallized from a mixture of methanol and diethyl ether and 1-benzyl-α,α-bis(α-chlorophenyl)imidazole-2-methanol with a melting point of 167-168°C was obtained.

The present invention also includes within its scope pharmaceutical compositions which as active ingredient contain at least one of the therapeutically active compounds of the general formula I or a non-toxic acid addition salt thereof, in connection with a pharmaceutically acceptable carrier. The compositions can have any of the forms that are usually used for the administration of therapeutic substances. Tablets and pills may be formulated in the usual manner with one or more pharmaceutically acceptable diluents or fillers, e.g. lactose or starch, and includes substances of a lubricating nature, e.g. calcium or magnesium stearate. Capsules, made of an absorbable substance such as gelatin, may contain the active substance alone or in admixture with a solid or liquid diluent.

The active substance or an acid addition salt thereof may also be present

in a form suitable for parenteral administration, i.e. as a suspension or emulsion in sterile water or an organic liquid which is usually used for injectable preparations such as e.g. a vegetable oil such as olive oil or a sterile solution in water or an organic solvent.

The following example shall illustrate the production of

a pharmaceutical composition.

EXAMPLE XLVIII

50 g of α,α-bis(p_-chlorophenyl)imidazole-2-methanol, sieved

through a 40 mesh sieve (opening size 0.345 mm), 50 g "Avicel PH

101" (microcrystalline cellulose) and 1 g of "Aerosil" (very pure silicon dioxide) are mixed together and gelatin capsules are filled with 101 mg of the mixture so that each capsule contains 50 mg of active substance.

Claims (1)

1. Arialogy method for the preparation of therapeutically active α,α-diarylimidazole-2-methanols of the general formula where R-^-R-j^q are the same or different and mean a hydrogen atom or a halogen atom or a trifluoromethyl or tertiary butyl group, provided that at least one of them is halogen, trifluoromethyl or tertiary butyl, R-j^ and R ^ are' the same or different and each means a hydrogen atom, a lower alkyl group, a phenyl group or a halogen-substituted phenyl group and R-^ means a hydrogen atom or a lower alkyl group, a lower alkoxymethyl group, a phenyl lower alkyl group (optionally substituted in the phenyl part by a halogen atom), a lower alkenyl group, a phenyl-lower-alkoxymethyl group or a toluene-p-sulfonyl group, as well as acid addition salts thereof, characterized in that a) a compound with the formula: where R,,- denotes an alkali metal atom or a reactive organo-metal group, R^^ is identical to R-^ except for a hydrogen atom, or a removable group beyond the scope of R-^ and R-^ and R 12 is as indicated above 5 reacted with a compound of the general formula: where R^ - R-^q are as defined above, and the group or atom R-j^ is removed from the resulting organo-metallic complex by hydrolysis to obtain a desired tertiary alcohol of the general formula I in claim 1 wherein R-^-j denotes a hydrogen atom or a corresponding compound bearing a substituent group R^^ on a nitrogen atom of the imidazole nucleus and, when in the latter case the substituent group is not identical to R-^ in the desired product, that the substituent group is removed and if desired a group within the definition for R , ., is introduced on. in a manner known per se and that the obtained base is, if desired, converted into an acid addition salt, or b) a compound of the formula: in which Rjji sr is a hydrogen atom or a group within the definition of R.^ or R-^, and the other R- symbols are as defined above, are converted with a compound of the formula: where the R symbols have the same meaning as above, where the group or atom R-^ is removed from the resulting organo-metallic complex by hydrolysis to obtain a desired tertiary alcohol of the general formula I wherein R-^ means a hydrogen atom or a corresponding compound which carries a substituent group R-j.3' on a nitrogen atom in the imidazole nucleus and, when in the latter case the substituent group is not identical to R-^ in the desired product, said substituent is removed, and if desired a group within the definition of R-^ is introduced on i and per se known manner, and that the obtained base is, if desired, converted into an acid addition salt, or c) when the compound according to formula I has the following meaning: in which the various R symbols are as indicated above and at least one of R^, B^, R^, R^ and R^ is halogen, trifluoromethyl or tertiary butyl, these are prepared by a compound of the general formula in which R, 7 means a halogen atom, an alkoxy, aryloxy, aralkyl or silyloxy group or a group OM in which M is a metal atom, and R-^ i' ^12°^ ^lA is as defined above, is reacted with a compound with the formula VII wherein the group or atom R^^ is removed from the resulting organo-metallic complex by hydrolysis to obtain a desired tertiary alcohol of the general formula I, wherein R-^^ means a hydrogen atom or a corresponding compound bearing a substituent group R-j^ on a nitrogen atom in the imidazole nucleus, and, when in the latter case the substituent group is not identical to R-^ in the desired product, said substituent group is removed, and if desired that a group is introduced within the definition of R-^ in and of itself known manner, and that the obtained base is, if desired, converted into an acid addition salt.