Compounds and process preparing a substituted or an unsubstitute

Details Compounds and process preparing a substituted or an unsubstitute Compounds and process preparing a substituted or an unsubstitute

1990-12-03

1993-03-02

Morris, Patricia L.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

5483355, C07D23364, C07D40510

Patent

active

051905892

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
The invention relates to a process for preparing a substituted or an unsubstituted 4(5)-(.omega.-aminoalkyl)imidazole, by brominating an .omega.-phthalimidoalkan-2-one to a 1- or 3-bromo-.omega.-phthalimido-alkan-2-one, subjecting said derivative to ring closure with an amidine, followed by hydrolytic separation of the phthalic residue.
2. Description of the Related Art
Such a process is already known from S. Elz and W. Schunack, Z.Naturforsch., 42b, 238-242 (1987).
Histamine H.sub.2 -receptor agonists, like Impromidine(1) described in Proc. VIIIth Internat. Symp. Med. Chem., Uppsala, pp. 202-203 (1985), editors R. Dahlblom and J. L. G. Nilson, SK&E 91486 (2) described by M. E. Parsons et al., Agents and Actions. 5, 464 (1975) and N-(.omega.-substituted alkyl)-N'-{(imidazole-4-yl)-alkyl)} guanidines, described in Dutch patent application 86 01585 and indicated therein with formula 1, all contain under physiological conditions a protonated "substituted" N-{.omega.-(imidazole-4-yl)alkyl}guanidine fragment which is essential for the biological activity of this type of compounds.
For the preparation of these and other H.sub.1 and H.sub.2 -receptor active compounds the 4(5)-(2-aminoethyl)imidazole or histamine (3) and 4(5-(3-aminopropyl)imidazole(4), in general the substituted 4(5)-(.omega.-aminoalkyl)imidazoles (5) are of crucial importance as starting materials for the preparation of the above mentioned H.sub.1 and H.sub.2 -receptor active compounds, so that in the field of pharmaceutical industry they are highly interested in the preparation of this kind of compounds, in view of pharmaceutical composition for the treatment of heart failures and allergic conditions.
Tedious syntheses of 4(5)-(3-aminopropyl)imidazole (4) starting form one of the two difficult obtainable compounds 4(5)-(2-bromoethyl)imidazolium bromide and 4(5)-(2-chloroethyl)imidazolium chloride as described by W. Bloemhoff, and K. E. T. Kerling, Rec. Trav. Chim., 89, 1181-1184 (1970), followed by chain extension with sodium cyanide or potassium cyanide and by reduction of the obtained nitrile with hydrogen and Raney Nickel catalyst as described in German Offenlegungsschrift 2 053 175, results in almost unacceptable low overall yields of the desired 4(5)-(3-aminopropyl)imidazole (4).
In the process described by S. Elz and W. Schunack Z. Naturforsch., 42b, 238-242 (1987) in the preamble, the bromination of 5-phthalimidopentane-2-one to 1-bromo-5-phthalimidopentane-2-one (6) is carried out in a b-butanol/methanol mixture with an equivalent bromo/dioxane complex which results in a yield of only 22%. The following ring closure in liquid NH.sub.3 under elevated pressure, followed by isolation of the desired imidazole via the dipicrate is impracticable in large scale syntheses.
Preparation of the corresponding halogen compounds from the corresponding diazoketones as described by J. Michalsky, J. Borkovec and J. Hadacek, Chem. Listy Vedu Prum. 49, 1979 (1955), cf. Chem. Abstr. 50, 5681d (1956) does not lend itself for large scale syntheses, and the bromination as described by E. W. Garbisch Jr., J. Org. Chem. 30, 2109 (1965) for the 3-phthalimidopropan-2-one, according to M. Gall and B. V. Kamdar, J. Org. Chem. 46, 1575-1585 (1981) does not lend itself for scale enlargement.
Alternatively the ring closure of a 1-bromo-.omega.-phthalimidoalkan-2-one with an amidine as mentioned for the preparation of 2-methylhistamine under the reaction conditions reported by Durant et al., J. Med. Chem., 19(7), 923-928 (1976) is not very advantageous due to low yields obtained in this procedure.


SUMMARY OF THE INVENTION

It was now found that with the process as described in the preamble a much higher yield can be reached than disclosed in the state of the art, when certain reaction conditions are taken into account towards bromination and the ring closure. In this process the bromination proceeds with great selectively, which enhances the yield highly, in addition the process is suitable for large scale applic

REFERENCES:
patent: 4119781 (1978-10-01), Lewis et al.
Durant, et al. J. Med. Chem., vol. 19, No. 7, pp. 923-928 (1976).
Gaudry et al., Tetrahedron, vol. 26, No. 23, pp. 5611-5615 (1970).
Elz, et al., Z.Naturforsch., 42b, 238-242 (1987).

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