Process for the preparation of substituted prolyl peptides and similar peptidomimetics

Abstract

The present invention relates to a process for the stereoselective preparation of a compound having the general formula (I) or its respective diastereomers: comprising reacting a compound having the general formula (II) or its diastereomers: with a compound of the general formula III: R3—COOH and a compound of the general formula IV: R4—NC wherein R1 represents each independently, or jointly a substituted or unsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic structure, and R2 represents a hydrogen atom, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic structure, and R3 represents a substituted or unsubstituted alkyl, alkenyl, or alkynyl, or an aromatic or non-aromatic aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic structure.R3—COOH  (III)R4—NC  (IV)

Description

FIELD OF THE INVENTION[0001]The present invention relates to substituted prolyl peptides and similar peptidomimetics, methods for their preparation, and a variety of uses including as inhibitors of disease-associated targets as well as an organocatalyst component.BACKGROUND TO THE INVENTION[0002]Optically pure 3,4-substituted prolyl peptides and related peptidomimetic compounds are of considerable interest in organocatalysis and medicinal chemistry, specifically since they form key structural elements of the hepatitis C virus NS3 protease inhibitors telaprevir and boceprevir as disclosed in for instance WO2003 / 062265.[0003]Multicomponent reactions (MCRs) offer the ability to rapidly and efficiently generate collections of structurally and functionally diverse organic compounds. Although MCRs are very efficient by their nature, the stereocontrol in these reactions is mostly not trivial.[0004]The Ugi reaction is undoubtedly one of the most widely applied MCRs. It is of considerable in...

AI Technical Summary

Benefits of technology

[0050]The term “stereoselective” refers to the preferential formation in a chemical or enzymatic reaction of one stereoisomer over another. Stereoselectivity can be partial, where the formation of one stereoisomer is favoured over the other, or it may be complete where only one stereoisomer is formed. When the stereoisomers are enantiomers, the stereoselectivity is referred to as enantioselectivity, the fraction reported as a percentage of one enantiomer in the sum of both. It is commonly alternatively reported in the art (typically as a percentage) as the enantiomeric excess (e.e.) calculated therefrom according to the formula [major enantiomer−minor enantiomer] / [major enantiomer+minor enantiomer]. Where the stereoisomers are diastereoisomers, the stereoselectivity is referred to as diastereoselectivity, the fraction (typically reported as a percentage) of one diastereomer in a mixture of two diasteromers, commonly alternatively reported as the diastereomeric excess (d.e.). Enantiomeric excess and diastereomeric excess are types of stereomeric excess. The present process allows a stereoselective preparation of the desired compounds in a simple an convergent manner, yielding the desired enantiomers—or diastereomers based on easily available chiral information preferably derived from 3R,4S- or 3S,4R-configured pyrrolidine compounds.

[0053]“Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.

[0061]Unlike prior art processes for the enantioselective preparation of compounds according to formula (I), the process of the present invention allows for the synthesis of either enantiomer of according to formula (I) in excellent yield and enantiomeric excess at mild conditions, and in a very small number of steps. In addition, the inventive process of the present invention allows for very effective use of readily available chiral starting information. Insofar, the process of the present invention is highly efficient as it does not produce 50% of the unwanted enantiomer. These advantages combine to make the process of the present invention very economic and amenable to industrial scale up.

[0062]The process according to the invention advantageously allows for the enantioselective formation of products, i.e., may produce products having a high enantiomeric excess. An “enantioselective” process according to the invention hence results in the formation of a product with an enantiomeric excess and / or diastereomeric excess of the desired respective enantiomer or diastereomers.

Problems solved by technology

However, as in most MCRs, controlling the newly formed stereocenter proves highly complex, and therefore the reaction suffers from poor and / or unpredictable (dia)stereoselectivity, as illustrated for instance by WO2006 / 061585.

The reported products are formed in only limited yields and mostly unpredictable diastereoselectivity, while requiring the use of protecting groups that are often difficult to remove, such as benzyl groups.

Accordingly, the known multicomponent reactions for the preparation of proline derivative comprising peptides and peptidomimetics suffer from poor and / or unpredictable (dia)stereoselectivity.

Alternative process schemes are tedious, require numerous steps and hence suffer from low yields.

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