Process for making functionalized oxazolidinone compounds

Details Process for making functionalized oxazolidinone compounds Process for making functionalized oxazolidinone compounds

2001-11-08

2003-10-21

McKane, Joseph K. (Department: 1639)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06635769

ABSTRACT:

FIELD OF THE INVENTION
The subject invention relates to processes for making certain functionalized oxazolidinone compounds.
SUMMARY OF THE INVENTION
The subject invention involves processes for making compounds having the structure:
wherein:
(a) R1 and R2 are each independently selected from hydrogen, alkyl, aryl and heterocycle, or R1 and R2 are attached to form a cycloalkyl, aryl or heterocyclic ring;
(b) R3 is selected from primary and secondary alkyl (—R6), —SO
2
—R4, and—C(O)NH—R5;
(c) R4 is aryl; and
(d) R5 is alkyl or aryl;
the process comprising a reaction step carried out in a reaction mixture, wherein an oxazolidinone having the structure:
is reacted with an electrophile selected from R6-Br, R6-I, R4-SO
2
Cl, and R5-NCO; the reaction mixture comprising a non-protic and non-oxidizing solvent and potassium fluoride on alumina; and without the presence of a substantial amount of a strong base in the reaction mixture.
DESCRIPTION OF THE INVENTION
Glossary of Terms
As used herein unless specified otherwise, “alkyl” means a hydrocarbon chain which is branched, linear or cyclic, saturated or unsaturated (but not aromatic), substituted or unsubstituted. The term “alkyl” may be used alone or as part of another word where it may be shortened to “alk” (e.g., in alkoxy, alkylacyl). Preferred linear alkyl have from one to about twenty carbon atoms, more preferably from one to about ten carbon atoms, more preferably still from one to about six carbon atoms, still more preferably from one to about four carbon atoms; most preferred are methyl or ethyl. Preferred cyclic and branched alkyl have from three to about twenty carbon atoms, more preferably from three to about ten carbon atoms, more preferably still from three to about seven carbon atoms, still more preferably from three to about five carbon atoms. Preferred cyclic alkyl have one hydrocarbon ring, but may have two, three, or more, fused or spirocycle hydrocarbon rings. Preferred alkyl are unsaturated with from one to about three double or triple bonds, preferably double bonds; more preferably they are mono-unsaturated with one double bond. Still more preferred alkyl are saturated. Saturated alkyl are referred to herein as “alkanyl”. Alkyl unsaturated only with one or more double bonds (no triple bonds) are referred to herein as “alkenyl”. Alkyl unsaturated with one or more triple bonds are referred to herein as “alkynyl”. Preferred substituents of alkyl include halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, arnide, alkylarnide, arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides, sulfo, alkylsulfo, arylsulfo, sulfino, alkylsulfino, arylsulfino, phospho, alkylphospho, arylphospho, phosphino, alkylphosphino, arylphosphino, nitro, and cyano. Substituents of cycloalkyl also include cycloalkyl, aryl and heterocyclic rings which are fused or spirocycle with the initial cycloalkyl. Also, unsubstituted alkyl are preferred. An alkyl is bonded to another moiety at the “attaching carbon” of the alkyl. As used herein, “primary alkyl” means that the attaching carbon of the alkyl has two or three hydrogens bonded to it; “secondary alkyl” means that the attaching carbon has one hydrogen bonded to it; and “tertiary alkyl means that the attaching carbon has no hydrogens bonded to it.
As used herein, “heteroatom” means a nitrogen, oxygen, or sulfur atom.
As used herein, “alkylene” means an alkyl which connects two other moieties, “heteroalkylene” means an alkylene having one or more heteroatoms in the connecting chain.
As used herein unless specified otherwise, “aryl” means an aromatic hydrocarbon ring (or fused rings) which is substituted or unsubstituted. The term “aryl” may be used alone or as part of another word (e.g., in aryloxy, arylacyl). Preferred aryl have from six to about fourteen, preferably to about ten, carbon atoms in the aromatic ring(s), and a total of from about six to about twenty, preferably to about twelve, carbon atoms. Preferred aryl is phenyl or naphthyl; most preferred is phenyl (Ph). Preferred substituents of aryl include halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides, sulfo, alkylsulfo, arylsulfo, sulfino, alkylsulfino, arylsulfino, phospho, alkylphospho, arylphospho, phosphino, alkylphosphino, arylphosphino, nitro, and cyano. Substituents of aryl also include cycloalkyl and heterocyclic rings which are fused with the aryl ring or rings. Also, unsubstituted aryl are preferred.
As used herein unless specified otherwise, “heterocycle” or “heterocyclic” means a saturated, unsaturated or aromatic cyclic hydrocarbon ring (or fused rings) with one or more heteroatoms in the hydrocarbon ring(s). Preferred heterocycles have from one to about six heteroatoms in the ring(s), more preferably one or two or three heteroatoms in the ring(s). Preferred heterocycles have from three to about fourteen, preferably to about ten, carbon plus heteroatoms in the ring(s), more preferably from three to about seven, more preferably still five or six, carbon plus heteroatoms in the rings(s); and a total of from three to about twenty carbon plus heteroatoms, more preferably from three to about ten, more preferably still five or six, carbon plus heteroatoms. Preferred heterocycles have one ring, but may have two, three, or more, fused rings. More preferred heterocyclic rings include those which are one ring with 5 or 6 carbon plus heteroatoms in the ring with no more than three ring heteroatoms, no more than two of which are O and S. Still more preferred are such 5- or 6-ring atom heterocycles with one or two ring atoms being O or S and the others being C; or with one, two or three ring atoms being N and the others being C. Such preferred 5- or 6-ring atom heterocycles are preferably saturated, unsaturated with one or two double bonds, or aromatic. Such preferred 5- or 6-ring atom heterocycles are preferably a single ring; or fused with a 3- to 6-ring atom hydrocarbon ring which is saturated, unsaturated with one double bond, or aromatic (phenyl); or fused with another such 5- or 6-ring atom heterocyclic ring. Heterocycles are unsubstituted or substituted. Preferred heterocycle substituents are the same as for alkyl.
As used herein, “strong base” means an inorganic hydroxide base, alkyl-alkali metal (e.g., n-butyllithium), alkali metal hydride (e.g., sodium hydride), alkoxide salt (e.g., sodium methoxide), alkali metal amide (e.g., lithium diisopropyl amide), and the like.
As used herein, “substantial amount” means a sufficient amount of a specified material such that it effects a subject invention process in a measurable way.
As used herein, “non-protic and non-oxidizing solvent” means a solvent that does not dissociate to provide a substantial and measureable proton concentration, and does not have substantial oxidizing potential. Protic solvents include, for example, water, methanol, ethanol, dimethylformamide and the like. Oxidizing solvents include, for example, dimethylsulfoxide, and the like.
As used herein “combinatorial library” of compounds means a mixture of related compounds or a group of individual compounds, e.g. in separate wells of a reaction block, made substantially simultaneously by substantially the same process using a mixture of or individual related reactants to obtain related compounds.
Processes of the Invention
The subject invention processes involve the use of a solid supported reagent for the preparation of functionalized oxazolidinones, either individually or in libraries. As a class, oxazolidinones have been shown to possess a wide range of biological activity, including antidepressant, antihistaminic, antiftingal, antihypertensive, and antibacterial activity. A brief examination of the literature reveals that most common methods for the preparation of functionalized oxazolidinones require the use of strong bases (i.e. n-BuLi, NaH, et

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