Solid phase synthesis of heterocycles

• US 6,362,009 B1
• Filed: 11/21/1997
• Issued: 03/26/2002
• Est. Priority Date: 11/21/1997
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Munoz, Benito, Chen, Chixu
• Primary Examiner(s): Venkat, Jyothsna
• Assistant Examiner(s): BAKER, MAURIE GARCIA
• Application Number:
  US08/975,944
• Time in Patent Office: 1,586 Days
• Field of Search: 546/1, 546/249, 546/290, 546/297, 546/298, 546/299, 546/304, 546/310, 546/314, 546/347, 546/348, 436/518, 436/523-531, 530/333, 530/334, 544/98, 544/358, 435/DIG.49
• US Class Current: 506/30
• CPC Class Codes: C07D 211/86 Oxygen atoms

Abstract

Methods for solid phase and combinatorial synthesis using a resin activation/capture approach are provided. In particular, methods for the production of dihydropyridones, N-acyidihydropyridones, tetrahydropyridones, pyridines, aminopyridines, N-acyltetrahydropyridines and tetrahydropyridines compounds and libraries containing such compounds are provided. Methods for screening the libraries and compounds and pharmaceutical compositions containing compounds prepared by the methods are provided.

Claims

1. A method of solid phase synthesis, comprising:

(a) capturing a substrate on a solid support and activating the substrate to react with a reagent with which the unactivated substrate does not react; and

(b) reacting the activated substrate on the solid phase with the reagent to give an addition product, wherein;

the substrate is a heteroaryl compound containing at least one heteroatom that is nitrogen;

the solid support comprises a functional group that reacts with the nitrogen atom in the substrate to form a heteroarylium ion;

the heteroarylium is a heteroaryl compound wherein at least one of the heteroatoms is a positively charged nitrogen;

the reagent comprises an organometallic compound that, in the absence of the resin, does not react with the substrate;

the organometallic compound is a compound which is an alkali, alkaline earth or transition metal salt of an organic compound; and

the organic compound is selected from the group consisting of alkanes, alkenes, alkynes, aryls, arylalkanes, heteroaryls and heteroarylalkanes.

2. The method of claim 1, wherein a substituent on the substrate comprises an alkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, dialkylamino, diarylamino, alkylarylamino, alkylthio or arylthio group.

3. The method of claim 1, further comprising the step of:

hydrolyzing the addition product to give a ketone; and

wherein a substituent on the substrate comprises a heteroatom that is not substituted with a hydrogen.

4. The method of claim 3, further comprising the step of:

cleaving the ketone from the solid support.

5. The method of claim 4, wherein cleavage is effected by reaction with a metal alkoxide.

6. The method of claim 3, further comprising the step of:

modifying the ketone by a process comprising the step of 1,2-addition giving a modified substrate.

7. The method of claim 6, further comprising the step of:

cleaving the modified substrate from the solid support under acidic conditions.

8. The method of claim 7, wherein cleavage results in reduction of the modified substrate.

9. The method of claim 7, wherein cleavage results in oxidation of the modified substrate.

10. The method of claim 3, further comprising the step of:

modifying the ketone by a process comprising the step of 1,4-addition to produce a modified substrate.

11. The method of claim 10, further comprising the step of:

cleaving the modified substrate from the solid support under acidic conditions.

12. The method of claim 5, wherein:

the substrate is 2-unsubstituted-4-(R²)-pyridine, where R² is selected from the group consisting of alkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, dialkylamino, diarylamino, alkylarylamino, alkylthio and arylthio, and is not substituted further or is substituted at the 3, 5 or 6 positions with one or more Z substituents;

Z is selected from the group consisting of halogen, nitrile, nitro, formyl, alkyl, haloalkyl, polyhaloalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, arylalkoxy, dialkylaminoalkyl, diarylaminoalkyl, dialkylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, arylcarbonylamino, aryloxycarbonylamino, azido, alkylthio, arylthio, perfluoroalkylthio, thiocyano, isothiocyano, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl or diarylaminosulfonyl; and

the solid support comprises an acylating, sulfonylating or phosphorylating agent.

13. The method of claim 12, wherein:

the functional group on the solid support has the structure;

wherein;

R¹ is selected from the group consisting of alkylene, arylene, alkylarylene and arylalkylene, and is unsubstituted or substituted with one or more substituents designated Q;

Q is halogen, hydroxy, nitrile, nitro, formyl, mercapto, carboxy, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, arylalkoxy, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, arylcarbonylamino, aryloxycarbonylamino, azido, alkylthio, arylthio, perfluoroalkylthio, thiocyano, isothiocyano, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl or diarylaminosulfonyl, such that, when R¹ is alkylene or arylalkylene, R¹ is a chiral group possessing one or more stereogenic centers;

X¹ is halo, pseudohalo or carboxy;

W is carbon, sulfur or P(OR²⁰), where R²⁰ is alkyl, aryl or arylalkyl;

h is 0-2;

s is 0 or 1; and

is a solid support.

14. The method of claim 13, wherein:

R² is selected from the group consisting of alkoxy, aryloxy, arylalkoxy, heteroaryloxy and heteroarylalkoxy;

R¹ is alkylene;

X¹ is halo;

W is carbon;

h is 1; and

s is 1.

15. The method of claim 14, wherein:

R² is alkoxy;

R¹ is methylene; and

X¹ is chloro.

16. The method of claim 15, wherein R² is methoxy.

17. The method of claim 1, wherein

the reagent is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl magnesium halide, lithium and cadmium reagents.

18. The method of claim 1, wherein:

the substrate is a 2-unsubstituted-4-(R²)-pyridine, where R² is selected from the group consisting of alkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, dialkylamino, diarylamino, alkylarylamino, alkylthio and arylthio, and is not substituted further or is substituted at the 3, 5 or 6 positions with one or more Z substituents; and

each Z is independently halogen, nitrile, nitro, formyl, alkyl, haloalkyl, polyhaloalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylidine, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, arylalkoxy, dialkylaminoalkyl, diarylaminoalkyl, dialkylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, arylcarbonylamino, aryloxycarbonylamino, azido, alkylthio, arylthio, perfluoroalkylthio, thiocyano, isothiocyano, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl or diarylaminosulfonyl.

19. The method of claim 1, further comprising:

(c) modifying the addition product to give a modified substrate; and

(d) optionally cleaving the addition product or modified substrate from the solid support;

wherein;

the substrate is selected from the group consisting of pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, pyridazine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine, acridine, perimidine, phenanthroline and phenazine, and is unsubstituted or is substituted with one or more Z substituents;

each Z is independently halogen, nitrile, nitro, formyl, alkyl, haloalkyl, polyhaloalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylidine, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, arylalkoxy, dialkylaminoalkyl, diarylaminoalkyl, dialkylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, arylcarbonylamino, aryloxycarbonylamino, azido, alkylthio, arylthio, perfluoroalkylthio, thiocyano, isothiocyano, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl or diarylaminosulfonyl;

wherein;

modification of the addition product comprises the processes of electrophilic substitution, nucleophilic addition and enolate alkylation;

cleavage of the addition product from the solid support comprises treatment with acid or base and optionally with an oxidant or reductant;

the substrate is a 2-unsubstituted-4-(R²)-pyridine, where R² is selected from the group consisting of alkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, dialkylamino, diarylamino, alkylarylamino, alkylthio and arylthio, and is not substituted further or is substituted at the 3, 5 or 6 positions with one or more Z substituents;

the reagent is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl magnesium halide and lithium reagents;

the acid is trifluoroacetic acid;

the base is sodium methoxide;

the oxidant is O₂; and

the reductant is triethylsilane.

20. The method of claim 13, wherein:

R² is selected from the group consisting of alkoxy, aryloxy, arylalkoxy, heteroaryloxy and heteroarylalkoxy;

R¹ is alkylene; and

X¹ is chloro.

21. The method of claim 20, wherein R² is alkoxy and R¹ is methylene.

22. The method of claim 20, wherein R² is methoxy.

23. The method of claim 1, wherein the resulting product is selected from the group consisting of dihydropyridones, N-acyldihydropyridones, tetrahydropyridones, pyridines, aminopyridines, N-acyltetrahydropyridines and tetrahydropyridines.

24. The method of claim 23, wherein the product is selected from compounds that have the formulae:

wherein;

R³ is alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;

R⁴ is selected from hydrogen, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, halo, amino, azido, cyano, nitro, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylalkylcarbonyl, heteroarylalkylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, arylalkoxycarbonyl, heteroarylalkoxycarbonyl, thio, alkylthio and arylthio, and may be further substituted with one or more Z substituents;

each Z is independently halogen, nitrile, nitro, formyl, alkyl, heloalkyl, polyhaloalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, arylalkoxy, dialkylaminoalkyl, diarylaminoalkyl, dialkylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, arylcarbonylamino, aryloxycarbonylamino, azido, alkylthio, arylthio, perfluoroalkylthio, thiocyano, isothiocyano, alkylsufinyl, alkylsufonyl, arylsufinyl, arylsufonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosylfonyl or diarylaminosulfonyl;

R⁷ is alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxy, aryloxy, arylalkoxy or heteroaylalkoxy; and

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, aryl, heteroayl, arylalkyl or heteroarylalkyl, or together form alkylene or alkenylene.