Processes for preparing imidazole derivatives and salts thereof

Details Processes for preparing imidazole derivatives and salts thereof Processes for preparing imidazole derivatives and salts thereof

2003-02-06

2004-03-16

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06706888

ABSTRACT:

This application is based upon and claims priority from Korean Patent Application No. 2002-7231 filed Feb. 8, 2002, the contents of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for preparing an imidazole derivative or its salt, which is useful as an intermediate for the preparation of an anti-viral, an anti-fungal or an anti-cancer agent.
2. Description of the Related Art
An imidazole derivative, more specifically a 4(5)-hydroxyalkyl imidazole derivative, or its salt is useful as an intermediate for the preparation of an anti-viral, an anti-fungal or an anti-cancer agent (see, WO 99/28314, WO 99/27928, WO 00/23438 and WO 00/53596). For example, 4-(3-hydroxypropyl)-imidazole is a useful intermediate for the preparation of anti-cancer agents (WO 01/09128).
Imidazole derivatives or salts thereof may be prepared by various methods, for example, as disclosed in WO 97/18813; Holger Stark, et al.,
J. Med. Chem
., 1996, 39, 1220; G. A. A. Kivits. et al.,
Heterocyclic chem
., 1975, 12, 577; Jurg R. Pfister et al.,
J. Heterocyclic Chem
., 1981, 831; Arch. Pharm., 1974, 517; and S. W. Fox, et al.,
J. Am. Chem. Soc
., 1945, 496.
The process disclosed in WO 97/18813 may be summarized as illustrated in the following reaction scheme 1 :
In the above reaction scheme 1, Tr is a triphenylmethyl group.
In the process according to the reaction scheme 1, the starting material is relatively expensive and the reducing agent, lithium aluminum hydride (LiAlH
4
), needs to be handled under an anhydrous condition. Accordingly, the process in accordance with the reaction scheme 1 has difficulties to be applied to an industrial-scale mass production.
The process disclosed in Holger Stark, et al.,
J. Med. Chem
., 1996, 39, 1220 may be summarized as illustrated in the following reaction scheme 2:
In the above reaction scheme 2, Tr is a triphenylmethyl group.
The above process employs urocanic acid as a starting material, which is a very expensive reagent, and lithium aluminum hydride (LiAlH
4
) as a reducing agent, which is unfavorable for industrial-scale mass production. Further, several complicated reactions are involved in the process. Accordingly, the process in accordance with the reaction scheme 2 has also difficulties to be applied to an industrial-scale mass production.
The process disclosed in G. A. A. Kivits. et al.,
Heterocyclic chem
., 1975, 12, 577 and Jurg R. Pfister, et al.,
J. Heterocyclic Chem
., 1981, 831 may be summarized as illustrated in the following reaction scheme 3:
In the above reaction scheme 3, R is hydrogen or methyl; m is 1 or 2.
The reaction, as shown in the reaction scheme 3, is carried out at a high temperature, such as 165° C., which causes degradation of the reactant and the product. Such degraded compounds may be changed into a tar, which makes it difficult to isolate and purify the product, thereby lowering the yield thereof. Further, the process employs formamide, thus, in order to remove un-reacted formamide remaining in the reaction system, multi-step isolation process, such as vacuum distillation, ion-exchange adsorption, and silica gel column chromatography, should be performed. Accordingly, the process in accordance with the reaction scheme 3 is difficult to apply to an industrial-scale mass production.
The process disclosed in
Arch. Pharm
., 1974, 517 may be summarized as illustrated in the following reaction scheme 4:
The process according to the reaction scheme 4 is relatively simple and the yield of the product is relatively moderate. However, mercury sulfate (II) (HgSO
4
) for the preparation of 1,4-dihydroxy-butan-2-one is very toxic, which causes a serious problem in post-treatment. Further, the immidazole-cyclization step needs an additional high-pressure reactor.
The process disclosed in S. W. Fox, et al.,
J. Am. Chem. Soc
., 1945, 496 may be summarized as illustrated in the following reaction scheme 5:
In the above process according to the reaction scheme 5, the yield of oxime intermediate is very low (i.e. less than 10%), so that the yield of the final product, 4-methyl-5-(&bgr;-hydroxyethyl)imidazole, is also very low.
SUMMARY OF THE INVENTION
The present invention provides a process for preparing an imidazole derivative or its salt in high purity and yield under a mild condition, so as to be favorably applied to a large-scale mass production thereof.
In one aspect of the present invention, there is provided a process for preparing a compound of formula 1 or its salt, which comprises reacting a compound of formula 2 with formamidine or its salt in the presence of a base:
wherein, R
1
and R
2
are respectively hydrogen, C
1
~C
4
alkyl, or a phenyl group; R
3
is an oxygen-containing leaving group or halogen; R
4
is halogen; and n is 1 or 2.
The above and other features and advantages of the present invention will become more apparent by describing in detail a preferred embodiment thereof.
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, an imidzole derivative or its salt is prepared in high purity and yield by reacting a compound of formula 2 with formamidine or its salt in the presence of a base. The resulting compound may be further purified and isolated to give a compound of formula 1 or its salt.
The salt of the compound of formula 1 may be produced in the forms of an organic acid salt or an inorganic acid salt, e.g., in salt forms of hydrochloride, hydrobromide, sulfuric acid, sulfonic acid, acetic acid, maleic acid, oxalic acid, picric acid, salicylic acid, p-toluenesulfonic acid, or methansulfonic acid, etc.
The compound of formula 2, which is a starting material in the process of the present invention, may be prepared by a method which is known in the art (Cecilia H. Marzabadi, et al.,
J. Org. Chem
., 1993, 58, 3761~3766; Athelstan L. J. Beckwith,
J. Chem. Soc
. Perkin Trans, 1993, 1673; Emile M. Gaydou,
Tetrahedron Letters No.
40, 4055~4058, 1972; M, Smietana,
Tetrahedron Letters
, 193~195, 2000; Shelton J. R.,
J. Org. Chem
., 1958, 23).
In the compound of formula 2, R
3
is halogen or an oxygen-containing leaving group. The oxygen-containing leaving group is a leaving group containing oxygen atom, such as hydroxy, acetoxy, methansulfonyloxy, p-toluensulfonyloxy, and etc.
The formamidine salt may be formamidine acetate or formamidine hydrochloride, which are commercially available. The amount of the formamidine or its salt is preferably about 1~10 eq., more preferably 2~5 eq., to 1 eq. of the compound of formula 2.
The base may be selected from the group consisting of a secondary amine, a tertiary amine, sodium acetate, sodium carbonate, sodium bicarbonate, potassium acetate, potassium carbonate, and potassium bicarbonate. The secondary amine includes diethylamine, 1,5-diazabicyclo[4,3,0]non-5-ene, and 1,8-diazabicyclo[5,4,0] undec-7-ene and the tertiary amine includes triethylamine, pyridine, and diisopropylethylamine. Among them, considering purity and yield of the product, diethylamine or potassium carbonate is preferable. The amount of the base is preferably about 2~5 eq. to 1 eq. of the compound of formula 2.
Although a reaction temperature in the process of the present invention is dependent on a reactant and a solvent employed, the reaction may be performed preferably at 70° C.~100° C., more preferably at 85° C.~95° C., considering purity and yield of the product. The reaction may be completed preferably in about 1~20 hours, more preferably about 2~6 hours.
The reaction of the present invention can be performed in the presence or absence of a solvent. For example, when a liquid base such as diethylamine is to be used, the reaction of the present invention can be performed without a solvent. When a solvent is to be used, examples of solvent include methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, dichloromethane, ethyl acetate, 1,4-dioxane, toluene, 2-ethoxyethanol, ethylene glycol, N,N-dimethylformamide, and dimethylsulfoxide. Among them, considering solubility

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