Process for preparing 1-alkyaryl-2-alkyl-5-formylimidazole

This invention relates to a process for preparing 1-alkylaryl-2-alkyl-5-formylimidazoles of the formula (I): ##STR1## which are useful intermediates in the preparation of 1,2,5-substituted imidazoles having angiotensin II receptor antagonist activity.

This application is a of U.S. Pat. No. 931/08390 filed Sep. 7, 1993. 
The present invention relates to a process for preparing useful 
intermediates in the synthesis of substituted imidazole compounds. Such 
compounds are described in EP Application No. 90 306 204.0 as being 
angiotensin II receptor antagonists useful in the treatment of 
hypertension, congestive heart failure, renal failure, and glaucoma. 
BACKGROUND OF THE INVENTION 
EP Application No. 90 306 204.0 describes a process for the preparation of 
imidazole intermediates which comprises a high pressure liquid ammonia 
condensation of an alkyl alkylimidate with dihydroxyacetone to give 
2-alkyl-5hydroxymethylimidazoles. Subsequent N-alkylarylation and 
oxidation yields 1-alkylaryl-2-alkyl-5-formylimidazoles. Although this 
process produces the key imidazole intermediates necessary for preparing 
the angiotensin II receptor antagonizing imidazoles described therein, the 
high pressure step limits the quantity of compound that can be produced 
using this method. Therefore, there is a need for an alternate method for 
the preparation of the imidazole intermediates on a commercial scale. 
A further challenge in developing an alternate process is the fact that the 
regiospecific synthesis of N-substituted imidazoles is not a straight 
forward operation. Few syntheses exist which result in the exclusive 
formation of 1,2,5-substitution on the imidazole ring. 
It has now been found that the substituted 5-formylimidazole intermediates 
can be prepared by reacting a 2-halo-2-propenal-3-alkyl ether,-3-alkyl 
thioether, or -3-amine with a N-( 1-iminoalkyl)aminoalkylaryl compound to 
produce said intermediates efficiently in high yield and high purity. The 
efficiency of the process and the quality and yields of the imidazole 
intermediates are particularly important when preparing compounds on a 
large scale for therapeutic use.

DESCRIPTION OF THE INVENTION 
The present invention provides a process for the preparation of a compound 
of formula (I): 
##STR2## 
wherein: R.sup.1 is hydrogen, phenyl, biphenyl, or naphthyl, with each 
group being unsubstituted or substituted by one to three substituents 
selected from Cl, Br, F, I, C.sub.1 -C.sub.6 alkyl, nitro, A-CO.sub.2 
R.sup.6, tetrazol-5-yl, C.sub.1 -C.sub.6 alkyl, SO.sub.2 NHR.sup.6, 
NHSO.sub.2 R.sup.6, SO.sub.3 H, CONR.sup.6 R.sup.6, CN, SO.sub.2 C.sub.1 
-C.sub.6 alkoxy, hydroxy, SC.sub.1 -C.sub.6 alkyl, NHSO.sub.2 R.sup.6, 
PO(OR.sup.6).sub.2, NR.sup.6 R.sup.6, NR.sup.6 COH, NR.sup.6 COC.sub.1 
-C.sub.6 alkyl, NR.sup.6 CON(R.sup.6).sub.2, NR.sup.6 COW, W, SO.sub.2 W; 
R.sup.2 is hydrogen, C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, 
C.sub.3 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, or 
(CH.sub.2).sub.0-8 phenyl unsubstituted or substituted by one to three 
substituents selected from C.sub.1 -C.sub.6 alkyl, nitro, Cl, Br, F, I, 
hydroxy, C.sub.1 -C.sub.6 alkoxy, NR.sup.6 R.sup.6, CO.sub.2 R.sup.6, CN, 
CONR.sup.6 R.sub.6, W, tetrazol-5-yl, NR.sup.6 COC.sub.1 -C.sub.6 allyl, 
NR.sup.6 COW, SC.sub.1 -C.sub.6 alkyl, SO.sub.2 W, or SO.sub.2 C.sub.1 
-C.sub.6 alkyl; 
W is C.sub.q F.sub.2q+1, wherein q is 1-3; 
A is --(CH.sub.2).sub.n --,--CH.dbd.CH--,--O(CR.sup.4 R.sup.5).sub.m --, 
or--S(CR.sup.4 R.sup.5).sub.m --; 
each R.sup.4, R.sup.5 independently is hydrogen, C.sub.1 -C.sub.6 alkyl 
(unsubstituted or substituted by phenyl, biphenyl, naphthyl or C.sub.3 
-C.sub.6 cycloalkyl), phenyl, biphenyl, or naphthyl (each of which is 
unsubstituted or substituted by one to three substituents selected from 
Cl, Br, I, F, C.sub.1 -C.sub.6 alkyl, (C.sub.1 -C.sub.5 
alkenyl)CH.sub.2,(C.sub.1 -C.sub.5 alkynyl)CH.sub.2, C.sub.1 -C.sub.6 
alkoxy, C.sub.1 -C.sub.6 alkylthio, NO.sub.2, CF.sub.3, CO.sub.2 R.sup.6, 
or OH), C.sub.3 -C.sub.6 cycloalkyl, or phenyl(C.sub.1 -C.sub.2 alkyl) 
unsubstituted or substituted by phenyl; 
each R.sup.6 independently is hydrogen, C.sub.1 -C.sub.6 alkyl, or 
(CH.sub.2).sub.n phenyl; 
each n independently is 0-4; and 
each m independently is 1-4; or a pharmaceutically acceptable salt thereof, 
which comprises reacting a compound of formula (II): 
##STR3## 
wherein: R.sup.1, R.sup.2 and n are as defined above for formula (I), with 
a compound of formula (III): 
##STR4## 
wherein: X is Cl, Br, F, or I; and 
Y is --OR.sup.3, --SR.sup.3, or-N(R.sup.3).sub.2, wherein R.sup.3 is 
C.sub.1 -C.sub.6 alkyl, under basic conditions and in solvent and, 
thereafter, optionally forming a pharmaceutically acceptable salt. 
Preferably, the process can be used to prepare compounds of formula (I) in 
which: 
R.sub.1 is phenyl, biphenyl, or naphthyl, with each group being 
unsubstituted or substituted by one to three substituents selected from 
Cl, Br, F, CF.sub.3, C 1-C6alkyl, nitro, CO.sub.2 R.sup.6, OCR.sup.4 
R.sup.5 CO.sub.2 R.sup.6, tetrazol-5-yl, C.sub.1 -C.sub.6 alkoxy, hydroxy, 
CN, or SO.sub.2 NHR.sup.6 ; 
n is 1 or 2; and 
R.sup.2 is C.sub.2 -C.sub.8 alkyl. 
It should be noted that, as used herein, the terms alkyl, alkenyl, alkoxy 
and alkynyl mean carbon chains which are branched or unbranched with the 
length of the chain determined by the descriptor preceding the term. Also, 
the term alkylaryl means --(CH.sub.2).sub.n R.sup.1 wherein R.sup.1 and n 
are as defined for formula (I) compounds. 
In particular, the process can be used to prepare compounds of formula (I) 
in which R.sup.1 is phenyl or naphthyl substituted by CO.sub.2 R.sup.6, 
preferably CO.sub.2 H, n is 1, and R.sup.2 is C.sub.2 -C.sub.8 alkyl, 
preferably n-butyl. Most particularly, the process can be used to prepare 
4-[(2-n-butyl-5-formyl- 1H-imidazol- 1-yl)methyl]benzoic acid and 
4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl-methyl]naphthoic acid. 
Suitably, the reaction is carried out on compounds of formula (II) in which 
R.sup.1, R.sup.2, and n are as required in the desired formula (I) 
product. Preferably, the process is conducted with formula (II) compounds 
in which R.sup.1 is phenyl or naphthyl substituted by CO.sub.2 R.sup.6, 
preferably CO.sub.2 H, n is 1, and R.sup.2 is C.sub.2 -C.sub.8 alkyl, 
preferably n-butyl. 
Suitably, the reaction is carried out on compounds of formula (III) in 
which X is Cl, Br, F, or I, preferably Br, and Y is --O--C.sub.1 -C.sub.6 
alkyl, preferably iso-propyloxy. 
Preferably, the reaction is carried out by reacting a 
2-halo-2-propenal-3-alkyl ether, such as 
2-bromo-3-(1-methylethoxy)-2-propenal, with a 
N-(1-iminoalkyl)aminoalkylaryl compound, such as 
N-(1-iminopentyl)-4-(aminomethyl)benzoic acid or 
N-(1-iminopentyl)-4-(aminomethyl)naphthoic acid, in the presence of base, 
such as an inorganic base, for example, sodium or potassium carbonate, or 
sodium or potassium hydroxide, preferably potassium carbonate, in solvent, 
such as water/organic solvent mixture, for example, water and 
tetrahydrofuran, water and acetonitrile, or water and chloroform 
containing 1, 4, 7, 10, 13, 16-hexaoxacyclooctadecane (18-Crown-6), 
preferably water and tetrahydrofuran. Suitably, the reaction is carried 
out at a temperature of between about 10.degree. C. and about 80.degree. 
C., preferably between about 25.degree. C. and about 65.degree. C. 
Alternately, the reaction is carried out in the presence of an organic base 
and in an organic solvent. For example, a 2-halo-2-propenal-3-alkyl ether, 
such as 2-bromo-3-(1-methylethoxy)-2-propenal, is reacted with a 
N-(1-iminoalkyl)aminoalkylaryl compound, such as ethyl 
N-(1-iminopentyl)-4-(aminomethyl)benzoate or ethyl 
N-(1-iminopentyl-4-(aminomethyl)naphthoate, in the presence of an organic 
base, for example, triethylamine, diisopropylethylamine, or 
dimethylaminopyridine, preferably triethylamine, in an organic solvent, 
such as chlorinated hydrocarbons, for example, chloroform dichloromethane, 
or 1,2-dichloroethane, preferably chloroform. Suitably, the reaction is 
carried out at a temperature of between about 10.degree. C. and about 
80.degree. C., preferably between about 25.degree. C. and about 65.degree. 
C. 
Alternately, the reaction is carried out using the N-( 
1-iminoalkyl)-aminoalkylaryl compounds of formula (II) as the base. For 
example, a 2-halo-2-propenal-3-alkyl ether, such as 2-bromo-3-( 
1-methylethoxy)-2-propenal, is reacted with a 
N-(1-iminoalkyl)aminoalkylaryl compound, such as ethyl 
N-(1-iminopentyl)-4-(aminomethyl)benzoate or ethyl N-( 
1-iminopentyl)-4-(aminomethyl)naphthoate, in the presence of a catalytic 
amount of acetic acid, in an organic solvent, such as chlorinated 
hydrocarbons, for example, chloroform, dichloromethane, or 
1,2-dichloroethane, preferably chloroform. Suitably, the reaction is 
carried out at a temperature of between about 10.degree. C. to about 
80.degree. C., preferably between about 25.degree. C. and about 65.degree. 
C. 
The starting N-(1-iminoalkyl)aminoalkylaryl compounds of formula (II) are 
prepared by reacting an alkyl alkylimidate, R.sup.2 C(.dbd.NH)--O--C.sub.1 
-C.sub.6 alkyl, for example, methyl valerimidate, with an aminoalkylaryl 
compound, such as 4-(aminomethyl)benzoic acid. 
The starting 2-halo-2-propenal alkyl ether compounds of formula (III) are 
prepared by halogenation and deprotection of malonaldehyde bisdialkyl 
acetal, followed by O-alkylation of the 2-halo-malonaldehyde intermediate. 
The invention is illustrated by the following example. The example is not 
intended to limit the scope of this invention as defined hereinabove and 
as claimed hereinbelow. 
EXAMPLE 1 
Preparation of 4-[(2-n-Butyl-5-formyl-1H-imidazol-1-yl)methylbenzoic Acid 
i. Preparation of Methyl Valerimidate Hydrochloride 
A 10 gallon, glass-lined fixed reactor was charged with 7.0 kg (84.6 mol) 
of valeronitrile and 2.96 kg (92.2 mol, 1.1 eq) of methanol. The solution 
was stirred with cooling to about 5.degree. C. under an atmosphere of 
nitrogen. A flow of hydrogen chloride gas from a gas cylinder was bubbled 
into the solution below the surface of the mixture at a rate such that the 
reaction temperature did not exceed 15.degree. C. After about one hour, 
3.67 kg (101 tool, 1.19 eq) of hydrogen chloride had been disbursed from 
the gas cylinder and addition was stopped. Stirring was continued for an 
additional 18 h at 0.degree. C. Tert-butyl methyl ether (9.7 kg) was added 
to the suspension and stirring was continued for 3 h at 0.degree. C. The 
slurry was then centrifuged under an atmosphere of nitrogen. After drying 
overnight under nitrogen and for several hours under reduced pressure at 
ambient temperature the product weighed 9.66 kg (76% yield uncorrected for 
purity) and had amp of 91.degree.-92.degree. C. The crude product was 
hygroscopic and was stored in sealed bottles under nitrogen at -5.degree. 
C. 
ii. Preparation of N-(1-iminopentyl)-4-(aminomethyl)benzoic acid 
A 22 L, three-necked round bottom flask equipped with an air-powered 
mechanical stirrer was placed under a nitrogen atmosphere. The vessel was 
charged with methyl valerimidate hydrochloride (2.5 kg, 16 mol) and 
dimethylformamide (9.2 L). A thermometer was attached and the suspension 
cooled to 0.degree.-15.degree. C. with a cooling bath. Triethylamine (2.3 
L) was added to the reaction at such a rate so that the internal 
temperature did not exceed 25.degree. C. The cooling was stopped and the 
reaction was allowed to stir 1 hour. The reaction mixture was vacuum 
filtered using a Buchner funnel and a carboy (20 L). The filter cake was 
washed with additional dimethylformamide (1.0 L) and force-air dried for 
15 min. The combined filtrates were saved. Another clean 22 L, 
three-necked round bottom flask equipped as above was placed under 
nitrogen. The vessel was charged with the combined filtrates from above 
followed by triethylamine (1.6 L) and 4-(aminomethyl)benzoic acid (1.7 kg, 
11.5 mol). The thermometer was attached and the suspension was heated to 
an internal temperature of 65.degree. C. with a heating mantle and a 
temperature controller. The heating was continued for 20 hours. The 
reaction was cooled to ambient temperature and filtered to yield 2.5 kg of 
product; 92% uncorrected yield. 
iii. Preparation of 2-bromo9-malonaldehyde 
A 12 L, three-necked round bottom flask was equipped with an air-powered 
mechanical stirrer with shaft, paddle, adapter, and thermometer was 
charged with 2.75 L of water and 110 mL of 12 N hydrochloric acid (1.32 
mol). The addition funnel was charged with 2.5 kg of malonaldehyde 
bis(dimethyl acetal (15.24 mol) which was then added to the stirred 
aqueous mixture in one portion. Stirring was continued for 30 rain and a 
clear solution resulted. The reaction mixture was then cooled to 5.degree. 
C. using an ice-water bath. A 1 L addition funnel was charged with 790 mL 
of bromine (15.34 mol) and added to the reaction mixture at a rate such 
that the temperature did not exceed 25.degree. C. (approximately 30 min). 
The cooling bath was removed and the reaction mixture was allowed to stir 
at ambient temperature 1 hour. The reaction mixture is colorless to 
slightly yellow at this point. The solution was transferred to a 10 L 
round bottom flask and concentrated on the rotary evaporator at aspirator 
pressure (water bath 40.degree. C.) to approximately one-half the original 
volume. The reaction suspension was removed from the rotary evaporator and 
cooled at 10.degree. C. for 18 hour. Using a benchtop Buchner funnel and 
carboy (20 L), the resultant slurry was vacuum filtered. The solid was 
washed with 50% aqueous methanol (0.50 L) and force-air dried 2 hours. The 
mother liquor was returned to the 10 L round bottom flask and concentrated 
to approximately one-half its original volume. The flask was removed from 
the rotary evaporator and cooled (10.degree. C.) for 18 hours where 
additional solid emerged (331 g). The combined dried product was 
transferred to glass jars for storage to avoid contact with metal and was 
stored under refrigeration. This material was used as obtained; (2.0 kg, 
86% uncorrected yield). 
iv. Preparation of 2-bromo-3-(1-methylethoxy)-2-propenal 
With moderate agitation, a 20 gallon reactor system was charged with 
cyclohexane (29.12 L), 2-bromo-malonaldehyde (2.33 kg), p-toluenesulfonic 
acid monohydrate 43.94 g, and 2-propanol (4.65 L). The contents of the 
reactor were heated to allow for the removal of distillate under 
atmospheric pressure (jacket temp. 95.degree. C. and process temp. at 
66.4.degree. C.). A total of 16 L of distillate was removed from the 
reaction via the cooling tower. This represents approximately 47% of the 
total volume of cyclohexane/2-propanol (33.77 L) being removed from the 
reactor. The reaction solution was cooled to near ambient temperature and 
transferred to a 10 gallon reactor system at 40.degree. C. An additional 6 
L of distillate was removed under vacuum (.about.64 torr, jacket temp. 
62.degree. C., and reaction temp. 25.degree. C.). The mobile dark orange 
oil was drained from the vessel and transferred to a rotary evaporator 
receiver flask and further concentrated under house vacuum at 
.about.30.degree. C. using a rotary evaporator. About 0.2 L more of 
solvent was removed. Total product obtained was 3.072 kg (16 mol, 103% 
yield). The product was used as obtained in the next step. This material 
is unstable and must be kept in a freezer (&lt;-5.degree. C., under 
nitrogen). The shelve-life is about 2 weeks. 
v. Preparation of 4-[(2.butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid 
A 10 gallon, glass-lined fixed reactor was charged sequentially under 
nitrogen gas with tetrahydrofuran (17.96 L), 
N-(1-iminopentyl)-4-(aminomethyl)benzoic acid (2.2 kg, 9.4 mol), potassium 
carbonate (1.94 kg), and water (2.19 L). The suspension was then stirred. 
2-bromo-3-(1-methylethoxy)-2propenal (1.99 kg, 10.3 mol) was added in one 
portion using .about.0.3 L tetrahydrofuran as rinse. The stirred mixture 
was heated to reflux (63.degree. C.). Reflux was continued for 3 hours 
additional amounts of 2-bromo-3-(1-methylethoxy)-2-propenal (0.36 kg, 0.2 
mol) was added to the vessel using 0.1 L tetrahydrofuran as rinse. After 
4.0 hours reflux, additional 2-bromo-3-(1-methylethoxy)-2-propenal (0.18 
kg, 0.1 mol) was added to the vessel using 0.1 L tetrahydrofuran as rinse. 
After 7.0 hours total reflux time, the reaction was cooled to 25.degree. 
C. and allowed to stand overnight with stirring. Water (3.6 L) was added 
to the vessel to dissolve any solids present and the solution was stirred 
15 min. The solution was transferred to a 20 gallon, glass-lined fixed 
reactor. The original reactor was rinsed with 0.36 L of water which was 
also added to the 20 gallon vessel. This vessel was charged with ethyl 
acetate (21.5 L) and the suspension was stirred for 5 rain and then 
allowed to settle. The dark aqueous alkaline product layer was transferred 
to a carboy (20 L) then added to a gallon vessel. The 20 gallon vessel was 
charged with water (2.9 L) and the suspension was stirred 5 rain then 
allowed to settle. The bottom aqueous layer was collected and added to the 
10 gallon vessel while the top ethyl acetate layer was collected for 
disposal. The basic (pH 10.05) aqueous solution was acidified with 6 N 
hydrochloric acid (2.51 L) to pH 5.2 then was transferred to a 20 gallon 
vessel. The 10 gallon vessel was rinsed with methylene chloride (26 L) and 
added to the 20 gallon vessel. The contents of the vessel were stirred for 
10 min and the layers allowed to separate. The lower organic layer was 
transferred to a carboy (20 L). The 20 gallon vessel was charged with 4.3 
L of methylene chloride and stirred for 5 min and then allowed to settle. 
After the phases separated, the bottom phase was collected in a carboy. 
The procedure was repeated once more with 4.3 L of methylene chloride. The 
combined methylene chloride extracts were added to a 10 gallon vessel and 
water was added (2.9 L). The suspension was stirred for 5 min then allowed 
to settle. The bottom organic layer was collected and placed in a portable 
50 L glass tank. Under fast agitation, 0.67 kg of magnesium sulfate and 
0.13 kg of activated charcoal were added and the suspension was filtered 
through a Buchner funnel containing Celite.RTM. under vacuum. The 10 
gallon vessel was charged with the methylene chloride solution and the 
solvent was removed under vacuum until about 5 L remained. The reactor was 
then charged with 2-butanone (5.17 L) and solvent was removed under vacuum 
until the volume was 4-5 L. Ethyl acetate was added (13 L) and the 
suspension was stirred 16 hours. At this time, the solid was removed by 
filtration using a Buchner funnel under vacuum. The collected solid was 
rinsed with a mix of 2-butanone:ethyl acetate (10:90) and dried overnight 
under vacuum. The yield obtained was 1457 g (5.08 mol, 94.0% purity). 
It is to be understood that the invention is not limited to the embodiment 
illustrated hereinabove and the right to the illustrated embodiment and 
all modifications coming within the scope of the following claims is 
reserved.