Process for preparing a 1-substituted 5-hydroxymethyl imidazole

Details Process for preparing a 1-substituted 5-hydroxymethyl imidazole Process for preparing a 1-substituted 5-hydroxymethyl imidazole

2002-03-05

2003-10-07

Stockton, Laura L. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S341100

Reexamination Certificate

active

06630593

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a process for preparing a 1-substituted 5-hydroxymethylimidazole of the formula:
, wherein
R represents alkyl, hydroxyalkyl, allyl, or substituted or unsubstituted arylmethyl or diarylmethyl, and preferably, C
1-4
alkyl, hydroxyC
1-4
alkyl, allyl, benzyl, substituted benzyl such as halogen-substituted benzyl or 3,4-dioxymethylenebenzyl, or 2-arylmethyl.
More specifically, the present invention relates to a process for preparing compound of the above formula (1) from a 1-substituted 2-mercapto-5-hydroxymethylimidazole of the formula:
, wherein R is as defined above, which is prepared by reacting 1,3-dihydroxyacetone dimer of the formula:
, with an acid addition salt of amine of the formula:
RNH
2
  (4)
, wherein R is as defined above, and thiocyanate of the formula:
 M—SCN  (5)
, wherein M represents alkali metal, in the presence of a transition metal catalyst such as tungstic acid, etc. and an oxidizing agent.
BACKGROUND ART
The 1-substituted 5-hydroxymethylimidazole of the formula (1) and its intermediate, i.e. 1-substituted 2-mercapto-5-hydroxymethylimidazole of the formula (2) are key intermediates known to be useful for preparing various anticancer agents under development, especially, farnesyl transferase inhibitors[J. S. Ko, et al., PCT WO99/05 1 17 A1 19990204, p129].
Various processes for the preparation of the compound of the formula (2) have already been known in the literature. For example, according to the process disclosed in E-P 146228B1, 1985, the 1-substituted 2-mercapto-5-hydroxymethylimidazole is obtained in the yield of 68.2% as a pale brown powder by reacting 1,3-dihydroxyacetone dimer of the formula:
, as the starting material, with amine of the formula:
RNH
2
  (4)
, wherein R represents alkyl, allyl, arylmethyl or diarylmethyl, and thiocyanate of the formula:
M—SCN  (5)
, wherein M represents potassium,
in the mixture of an organic acid and a lower alcohol solvent.
However, under the above reaction conditions, there are some problems associated with the isolation of the product in good purity since an unidentified black tar is formed as a by-product and turned out to be difficult to purify.
For preparing compound of the formula (1) from compound of the formula (2), the known process, an oxidative desulfurization is conventionally performed by warming compound of the formula (2) in the presence of concentrated nitric acid, with or without the catalytic amount of nitrite[R. G. Jones, J. Amer. Chem. Soc., 1949, 71, 383]. This method is useful in the laboratory scale preparation. However, this process has some problems associated with safety in the industrial scale. These are evolution of environmentally toxic nitrogen oxide gas and difficult control of the reaction. In addition, if the compound of the formula (2) has an aromatic functionality, electrophilic aromatic nitration reaction on the aromatic ring is accompanied as a side reaction.
DISCLOSURE OF THE INVENTION
The present inventors performed extensive studies to develop a novel process for the preparation of a 1-substituted 5-hydroxymethylimidazole and its intermediate, a 1-substituted 2-mercapto-5-hydroxymethylimidazole. As a result, they have identified that the problems of the previous process for preparing compound of the formula (2) could be removed by replacing amine by its acid addition salt. That is, if the acid addition salt of amine such as ammonium chloride is used, the formation of the colored by-products are eradicated completely. Therefore, the desired compound, compound of the formula (2) can be obtained in high purity and yield.
In addition, since there are few practical examples of oxidative cleavage of thiol group, which allows to prepare compound of the formula (1) from compound of the formula (2), the present inventors made a research to develop a new process which could be viable in the industrial scale. Finally, they have identified that the desired imidazole derivative can be obtained in high purity under safe and environmentally benign reaction conditions by employing a transition metal catalyst and an oxidizing agent such as hydrogen peroxide and thus, completed the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Therefore, an object of the present invention is to provide a new process for the preparation of a 1-substituted 5-hydroxymethylimidazole of the formula (1) from 1-substituted 2-mercapto-5-hydroxymethyl imidazole of the formula (2).
The present invention relates to a process for preparing 1-substituted 5-hydroxymethylimidazole of the formula:
, wherein R represents alkyl, hydroxyalkyl, allyl, or substituted or unsubstituted arylmethyl or diarylmethyl, and preferably, C
1-4
alkyl, hydroxyC
1-4
alkyl, allyl, benzyl, substituted benzyl such as halogen-substituted benzyl or 3,4-dioxymethylenebenzyl, or 2-arylmethyl,
comprising the steps of reacting 1,3-dihydroxyacetone dimer of the formula:
, with an acid addition salt of amine of the formula:
RNH
2
  (4)
, wherein R is as defined above, and thiocyanate of the formula:
M—SCN  (5)
, wherein M represents alkali metal, in the presence of an acid catalyst in a lower alcohol solvent to prepare a 1-substituted 2-mercapto-5-hydroxymethylimidazole of the formula:
, wherein R is as defined above; and,
reacting the compound of the formula (2) in the presence of a transition metal catalyst and an oxidizing agent in a solvent.
As for the substituent “R”, however, any conventional substituents other than those as mentioned above may be applied without any explicit indication.
The term “alkyl” as used herein includes straight or branched chain alkyl.
The preparation process according to the present invention comprises 2 steps. The first step is that a 1-substituted 2-mercapto-5-hydroxymethylimidazole of the formula (2) is prepared by reacting 1,3-dihydroxyacetone dimer of the formula (3) with an acid addition salt of amine of the formula (4) and thiocyanate of the formula (5). The second step is that a 1-substituted 5-hydroxymethylimidazole of the formula (1) is prepared from the above compound of the formula (2) via oxidative desulfurization.
Therefore, the present invention relates to a process for preparing a 1-substituted 5-hydroxymethylimidazole of the formula:
, wherein R is as defined above,
by the reaction of compound of the formula:
, wherein R is as defined above,
in the presence of a transition metal catalyst and an oxidizing agent in a solvent.
Hereinafter, each step of the present process will be explained in detail.
In Step 1, a 1-substituted 2-mercapto-5-hydroxymethylimidazole of the formula
, wherein R is as defined above,
is prepared by reacting 1,3-dihydroxyacetone dimer of the formula:
, with an acid addition salt of amine of the formula:
RNH
2
  (4)
, wherein R is as defined above, and
thiocyanate of the formula:
M—SCN  (5)
, wherein M is as defined above,
in the presence of an acid catalyst in a lower alcohol solvent.
The above reaction is depicted in the following Reaction Scheme (1):
, wherein M and R are each as defined above.
The formation mechanism of imidazole compound of the formula (2) is depicted below(vide infra). Iminium intermediate is formed from dihydroxyacetone and amine, and tautomerized to &agr;-aminoaldehyde intermediate, which reacts with thiocyanate to give urea intermediate. Intramolecular cyclization and dehydration should afford compound of the formula (2).
In the above reaction scheme, R is as defined above.
Since it is assumed that impurity material should be formed by the reaction of reactive &agr;-aminoaldehyde intermediate and excessive amine, control of the concentration of free amine in a suitable level is thought to be the key factor for clean reaction. Therefore, in the present invention, the problems of the previous method are removed by lowering the concentration of free amine by the employment of an acid addition salt of amine.
More specifically, to prepare a 1-substituted 2-mercapto-5-hydroxymethylimidazo

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