Process for the preparation of compounds having ACE inhibitory a

Details Process for the preparation of compounds having ACE inhibitory a Process for the preparation of compounds having ACE inhibitory a

1996-02-15

1998-08-04

Richter, Johann

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

5483345, 5483791, 548409, 548428, 548452, 548535, 564428, C07D21130, C07D23326, C07D48702, C07D49500

Patent

active

057895970

DESCRIPTION:

BRIEF SUMMARY
This application is a 37-1 of PCT/SI95/00017 Jul. 13, 1995.


TECHNICAL FIELD

The present invention belongs to the field of the organic chemistry synthesis and refers to a process for the preparation of compounds having ACE inhibitory action as well as to novel compounds useful as starting materials or intermediates in the said process.


TECHNICAL PROBLEM

There was a need for a simple and industrially convenient process for the preparation of compounds having ACE inhibitory action.


PRIOR ART

In EP 0215335 there is disclosed a process for activating N-carboxyanhydride. The reaction yields are very high but the process necessitates the use of a highly toxic reagent for the preparation of an active intermediate. During the reaction phosgene polymers decompose to phosgene, which leaves the reaction medium. A fresh reagent must be added repeatedly. For carrying out the process, special industrial plants are necessary in order to prevent the contamination of environment. with organic and inorganic salts of L-proline. Reactions take place in a basic medium as to prevent possible reactions with the secondary amino group.
It is well-known from the literature that for the formation of N-carboxyanhydrides of amino acids also carbonyl diimidazole may be used as a synthon for the formation of phosgene. The yields of acylation reaction depend upon the organic solvents used and water in the reaction solution. In methanol the reaction yield is 41.4%, in dioxane 96% and in acetone 94%. The reaction results are determined by HPLC analysis.
In the said patent in the activation reaction of the starting N-carboxyanhydride is specified nor possible side reactions (J. Org. Chem., 32, 11, 1967) are mentioned. In the optimum Example 4 the reaction yield up to enalapril (base) is 87%. The separation of enalapril maleate is carried out with a 81.8% yield.
In U.S. Pat. No. 4,374,829 a process for the preparation of enalapril maleate by asymmetric reduction of the corresponding starting Schiff's base is disclosed. In different reaction conditions, however, always only a mixture of stereospecific isomers is isolated.
In ES patent 2,004,804 the preparation of carboxyalkyldipeptides useful as ACE inhibitors is disclosed. 1,1-carbonyldiimidazole in EtOAc and subsequently with L-proline and enalapril maleate is obtained with a 77% yield.
The first object of the invention is a process for the preparation of compounds having ACE inhibitory action of the formula ##STR2## and pharmaceutically acceptable salts thereof, wherein R has the following meanings ##STR3## characterized in that the carboxy group of the stereospecific amino acid ##STR4## is activated with thionyl chloride derivative of the formula I' ##STR5## or with thionyl chloride derivative of the formula II' ##STR6## wherein R.sub.1 is the residue of a heterocyclic ambident compound such as imidazole, benzimidazole, 2-methylimidazole or triazole, in the presence of an aprotic organic solvent under elimination of the precipitated hydrochloride of the above mentioned heterocyclic ambident compound, to the intermediate novel compound A ##STR7## or to the intermediate novel compound B ##STR8## and the obtained intermediate compound (A, B) is reacted with an amino acid, preferably in its monosilylated form, most preferably in a disilylated form, selected from the group consisting of ##STR9## whereat the reaction medium must be anhydrous in all steps, and then the obtained compounds are converted to pharmaceutically acceptable salts thereof in a conventional manner.
The starting stereospecific amino acid commercially available compound and is disclosed in EP 353350 A1 and in Spanish Patent Application 9400994.
As the thionyl chloride derivative of the formula I' useful as the activating reagent e.g. chlorothionylimidazole of the formula (I) ##STR10## may be used and as the thionyl chloride derivative of the formula II' useful as the activating reagent e.g. thionyldiimidazole of the formula (II) ##STR11## may be used.
The course of the activation of step of the inventive process usin

REFERENCES:
"Low Molecular Weight Proteins as Carriers for Renal Drug Targeting." Franssen et al., J. Med. Chem. 1992, 35, pp. 1246-1259.

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