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US 2002/0161234 A1Published application
Method of preparing intermediates useful in synthesis of retroviral protease inhibitors
AssigneeG.D. Searle & Co.
InventorsJohn S. Ng, Claire A. Przybyla, Richard A. Mueller, Michael L. Vazquez, Daniel P. Getman
Life of this patent
Estimating the term…
Abstract
A synthesis is described for intermediates which are readily amenable to the large scale preparation of hydroxyethylurea-based chiral HIV protease inhibitors. The method includes forming a diastereoselective epoxide from a chiral alpha amino aldehyde.
Claims20
A method of preparing an aminoepoxide compound of Formula I:
- 9
- wherein P1 and P2 independently are selected from acyl, aralkyl, alkenyl, silyl, aralkoxycarbonyl, alkoxycarbonyl and cycloalkenylalkyl;
- wherein further P1 and P2 may be taken together with the nitrogen atom of Formula I to form a heterocyclic ring system containing said nitrogen atom as a ring member;
- and wherein R1 is selected from alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl, which are optionally substituted with a group selected from alkyl, halo, NO2, OR9 and SR9, wherein R9 is selected from hydrogen and alkyl;
- and wherein any of the foregoing groups of P1, P2 and R1 may be substituted at one or more substitutable positions with one or more radicals independently selected from halo, alkyl of C1-C8, alkoxy, hydroxy, nitro, alkenyl, amino, alkylamino, acylamino and acyl;
- or a pharmaceutically-acceptable salt thereof;
- said method comprising the steps of forming a protected aminoalcohol, oxidizing said protected aminoalcohol to a chiral protected aminoaldehyde and diastereoselectively forming the aminoepoxide from said aminoaldehyde with an organometallic methylene-adding reagent in an appropriate solvent.
4 more elements
A diastereoselective and enantioselective method of preparing a protected chiral alpha-amino epoxide of Formula I:
- 10
- wherein P1 and P2 independently are selected from acyl, aralkyl, alkenyl, silyl, aralkoxycarbonyl, alkoxycarbonyl and cycloalkenylalkyl;
- wherein further P1 and P2 may be taken together with the nitrogen atom of Formula I to form a heterocyclic ring system containing said nitrogen atom as a ring member;
- and wherein R1 is selected from alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl, which are optionally substituted with a group selected from alkyl, halo, NO2, OR9 and SR9, wherein R9 is selected from hydrogen and alkyl;
- and wherein any of the foregoing groups of P1, P2 and R1 may be substituted at one or more substitutable positions with one or more radicals independently selected from halo, alkyl of C1-C8, alkoxy, hydroxy, nitro, alkenyl, amino, alkylamino, acylamino and acyl;
- or a pharmaceutically-acceptable salt thereof;
- said method comprising treating a protected aminoaldehyde substrate with an organometallic methylene-adding reagent in an appropriate solvent.
4 more elements
A method of forming protected alpha-aminoaldehyde of Formula III:
- 11
- wherein P1 and P2 independently are selected from acyl, aralkyl, alkenyl, silyl, aralkoxycarbonyl, alkoxycarbonyl and cycloalkenylalkyl;
- wherein further P1 and P2 may be taken together with the nitrogen atom of Formula III to form a heterocyclic ring system containing said nitrogen atom as a ring member;
- and wherein R1 is selected from alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl, which are optionally substituted with a group selected from alkyl, halo, NO2, OR9 and SR9, wherein R9 is selected from hydrogen and alkyl;
- and wherein any of the foregoing groups of P1, P2 and R1 may be substituted at one or more substitutable positions with one or more radicals independently selected from halo, alkyl of C1-C8, alkoxy, hydroxy, nitro, alkenyl, amino, alkylamino, acylamino and acyl;
- or a pharmaceutically-acceptable salt thereof;
- said method comprising treating at a temperature of about 0° C. to about 30° C. a protected aminoalcohol with an oxidizing agent.
4 more elements
A method of preparing protected chiral alpha-amino alcohol of the formula:
- 12
- wherein P1 and P2 independently are selected from acyl, aralkyl, alkenyl, silyl, aralkoxycarbonyl, alkoxycarbonyl and cycloalkenylalkyl;
- wherein further P1 and P2 may be taken together with the nitroaen atom of Formula II to form a heterocyclic ring system containing said nitrogen atom as a ring memner;
- and wherein R1 is selected from alkyl, aryl, cycloalkyl, cycloalkylalkyl and arylalkyl, which are optionally substituted at one or more substitutable positions with a group selected from alkyl, halo, NO2, OR9 and SR9, wherein R9 is selected from hydrogen and alkyl;
- and wherein any of the foregoing groups of P1, P2 and R1 may be substituted with one or more radicals independently selected from halo, alkyl of C1-C8, alkoxy, hydroxy, nitro, alkenyl, amino, alkylamino, acylamino and acyl;
- or a pharmaceutically-acceptable salt thereof;
- said method comprising treating said aminoalcohol with an alkylating agent.
4 more elements
Dependencies are inferred from the claim text.