Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1995-12-06
1999-12-21
Bernhardt, Emily
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
548250, C07D48718
Patent
active
060051051
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND
The present invention relates to a process for producing an imidazole derivative. More particularly, it relates to a process for producing an imidazole derivative represented by the chemical formula [I]: ##STR3## which is useful for hypertension, congestive heart failure, renal failure, glaucoma, hyperuricemia and the like, in which complicated steps are avoided.
The above compound is an angiotensin II antagonist and is thus useful as an agent for preventing or treating hypertension, congestive heart failure, renal failure, glaucoma, hyperuricemia and the like. The present inventors have found that drugs of this class have longer shelf life, higher activity, rapid manifestation of action upon intravenous injection, good absorbability into the body upon oral administration, lower toxicity and long-lasting action. These novel compounds are imidazole derivatives having the hydrazine cross-linking structure represented by the formula: ##STR4## as described in Japanese Patent Application No. 3-277537, No. 3-323474, No. 4-095191 and No. 4-216809 and published PCT application WO 93/08193, published Apr. 29, 1993, which claims the benefit thereof. In the above applications, we reported the imidazole derivative [I] represented by the chemical formula: ##STR5## had particularly good effects. And we disclosed, in the above patent applications and Japanese Patent Application No. 5-060067, that this imidazole derivative can be synthesized according to the following route (Reaction scheme 1). In the route, a compound (1) is first protected with benzyl group, and after a few steps, the protected compound is debenzylated by hydrogenolysis to give a compound (4) and thereafter, a biphenyltetrazole part is linked thereto to give an end compound [I]. However, the above route has the problems in production efficacy and economical properties. In this regard, Richard F. Shuman et al. reported an improved process for producing biphenyltetrazoles which are an intermediate useful for production of angiotensin II antagonist in U.S. Pat. No. 5,039,814. ##STR6##
INFORMATION DISCLOSURE
Methods of synthesis of compounds of the formula I are described in WO 93/08193, published Apr. 29, 1993. Another process is discussed in U.S. Pat. No. 5,039,814.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a process for producing an imidazole derivative having the excellent effects without passing through the complicated synthesis route.
The present inventors have studied the problems and have found that the imidazole compound can be prepared without passing through a reaction of deprotecting the benzyl group by introducing therein a p-halogenobenzyl group, which resulted in completion of the present invention.
That is, the present invention provides a process for producing an end compound [I] (Process A) which comprises introducing p-halogenobenzyl group in the compound (1) in place of protecting the compound (1) with benzyl group, subjecting the protected compound to the following route (Reaction Scheme 2) to give a compound (8), subjecting the resulting compound to cross-coupling with phenyltetrazole or suitably protected phenyltetrazole to construct a biphenyltetrazole part, and subjecting the resulting compound to diisobutylaluminium hydride (DIBAH) reduction, and a process for producing an end compound [I] (Process B) which comprises subjecting a compound (8) to diisobutylaluminium hydride reduction to give a compound (9), subjecting it to cross-coupling with phenyltetrazole or suitably protected phenyltetrazole to construct a biphenyltetrazole part. These processes do not need the complicated procedures such as protection with benzyl group, deprotection, synthesis of biphenyltetrazole, reaction with imidazole and the like. Further these processes have the advantages such that all the reactions are utilized effectively for construction of an end compound and respective steps have the higher yield. ##STR7##
As the alkyl group represented by a variable substituent R, there are methoxymethyl, methoxye
Fujita Yoshiji
Koh Keiko
Munesada Kiyotaka
Taniguchi Mikio
Tsuzuki Kazuo
Bernhardt Emily
Newtson Ruth H.
Pharmacia & Upjohn Company
Welch Lawrence T.
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