Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-03-22
1996-10-15
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D23364, C07D23390
Patent
active
055655777
DESCRIPTION:
BRIEF SUMMARY
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; 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; or--S(CR.sup.4 R.sup.5).sub.m --; (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; (CH.sub.2).sub.n phenyl; 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 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 unsubstituted or substituted by one to three substitue
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Mokhallalati Mohamed K.
Pridgen Lendon N.
Shilcrat Susan
Weinstock Joseph
Higel Floyd D.
Lentz Edward T.
McCarthy Mary E.
SmithKline Beecham Corporation
Venetianer Stephen
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