Process for making substituted 2-amino-thiazolones

A process for the preparation of a compound according to formula I, or a tautomer, stereoisomer, geometric isomer, or optical isomer thereof:

• comprising
• (a) asymmetrically alkylating a compound of formula II by contacting a compound of formula II
• with a chiral base selected from the group consisting of
• wherein
• X is selected from O, N, S, and C1-8-alkylene;
• Y is selected from C1-8-alkyl, aryl, and heterocyclyl;
• is selected from Li, Na, K, Cs, Cu, Zn, and Mg;
• and
• Ar is an aryl;
• and an alkylating agent R3-LG in the presence of an amine, whereby the compound of formula II is asymmetrically alkylated;
• wherein:
• Z is S or O;
• R1 is selected from C1-8 alkyl, C2-8 alkenyl, C3-10-cycloalkyl, C3-10-cycloalkenyl, C3-10-cycloalkyl-C1-8-alkyl, C3-10-cycloalkenyl-C1-8-alkyl, aryl, aryl-C1-8-alkyl, heterocyclyl, heterocyclyl-C1-8-alkyl and haloalkyl;
• wherein any aryl, cycloalkyl, or heterocyclyl residue is optionally independently substituted by one or more C1-8-alkyl, aryl, halogen, halo-C1-C8-alkyl, HO—C1-C8-alkyl, R4R5N—C1-C8-alkyl, C1-C8-alkyl-OR6, —OR6, (C3-C10)-cycloalkyl or C1-C8-alkyl-sulfonyl;
• R2 and R3 are independently selected from C1-8-alkyl, C1-8-alkoxy, C3-10-cycloalkyl, heterocyclyl, C3-10-cycloalkyl-C1-8-alkyl, CN—C1-8-alkyl, aryl, aryl-C1-8-alkyl, heterocyclyl-C1-8-alkyl and haloalkyl;
• wherein any aryl, cycloalkyl, or heterocyclyl residue is optionally independently substituted by one or more C1-8-alkyl, aryl, halogen, halo-C1-C8-alkyl, HO—C1-C8-alkyl, R4R5N—C1-C8-alkyl, C1-C8-alkyl-OR6, —OR6, (C3-C10)-cycloalkyl or C1-C8-alkyl-sulfonyl;
• R4 and R5 are each independently selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, —NR6R6, —S—(C1-C8)alkyl, aryl and heterocyclyl;
• where in the definition of R4 and R5 any alkyl, alkoxy, heterocyclyl or aryl may be substituted with one to three substituents selected from -halo, unsubstituted C1-C8 alkyl, unsubstituted C1-C8 alkoxy, unsubstituted C1-C8 thioalkoxy and unsubstituted aryl(C1-C4)alkyl
• R6 is independently selected from hydrogen, C1-C8 alkyl, aryl-C1-C8 alkyl, C1-C8 alkoxy, —S—(C1-C8)alkyl, heterocyclyl and aryl;
• where in the definition of R6 any alkyl, heterocyclyl or aryl may be substituted with one to three substituents selected from -halo, unsubstituted C1-C8 alkyl, unsubstituted C1-C8 alkoxy, unsubstituted C1-C8 thioalkoxy and unsubstituted aryl(C1-C4)alkyl
• LG is a leaving group;
• and
• (b) contacting the product of (a) with an acid HB to form a salt of formula I′, then isolating the salt of formula I′,
• wherein B is an organic or inorganic anion selected from the group consisting of acetate, 4,4-diaminostilbene-2,2-disulfonate, benzenesulfonate, benzonate, bicarbonate, bisulfate, borate, bromide, butyrate, carbonate, chloride, citrate, edetate, edisylate, estolate, esylate, fiunarate, fumarate, glycolate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydroxynaphthoate, iodide, isothionate, laurate, malate, maleate, mesylate, methylbromide, methylnitrate, methylsulfate, napsylate, nitrate, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, 1,1-methene-bis-2-hydroxy-3-naphthoate, phosphate, diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, teoclate, tosylate, triethiodide, trifluoroacetate, and valerate;
• and
• (c) reacting the salt of formula I′ that was isolated in step (b) with a base to form the compound of formula I
• wherein the disastereomeric excess (de) of the compound of formula I is at least 85%.