Synthesis of inhibitors of 11β-hydroxysteroid dehydrogenase type 1

A method of preparing an oxazinone compound represented by the following structural formula:

• wherein:
• R1 is (a) absent or (b) is selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, optionally substituted (C1-C3)alkoxy(C1-C3)alkoxy, and (C1-C3)alkoxy(C1-C3)alkyl, each of which is optionally substituted with 1 to 4 groups independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, benzyloxycarbonyl, hydroxy(C1-C4)alkyl, cyano(C1-C4)alkyl, (C1-C4)alkylamino, di(C1-C4)alkylamino, halogen, cyano, oxo, nitro, hydroxy, amino, MeSO2—, MeSO2N(Me)(C1-C4)alkyl, MeSO2NH(C1-C4)alkyl, H2NC(═O)CMe2(C1-C4)alkyl, H2NC(═O)CHMe(C1-C4)alkyl, H2NC(═O)CH2(C1-C4)alkyl, —OR, —NR2, —COOR, —CONR2, and —SOkR, wherein k is 0, 1 or 2, and wherein each R is independently —H, an alkyl group, a cycloalkyl group or an aryl group;
• E is (a) a bond or (b) (C1-C3)alkylene or (C1-C2)alkoxy, wherein the O is attached to R2, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl and oxo;
• R2 is selected from (C1-C6)alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is optionally substituted with 1 to 4 groups independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, benzyloxycarbonyl, protected hydroxy(C1-C3)alkyl hydroxy(C1-C4)alkyl cyano(C1-C4)alkyl (C1-C4)alkylamino di(C1-C4)alkylamino, halogen, cyano, oxo, nitro, hydroxy, amino, MeSO2—, MeSO2N(Me)(C1-C4)alkyl, MeSO2NH(C1-C4)alkyl, protected CONH2, protected carboxylic acid, H2NC(═O)CMe2(C1-C4)alkyl, H2NC(═O)CHMe(C1-C4)alkyl, H2NC(═O)CH2(C1-C4)alkyl, —OR, —NR2, —COOR, —CONR2, and —SOkR, wherein k is 0, 1 or 2, and wherein each R is independently —H, an alkyl group, a cycloalkyl group or an aryl group;
• R3 is selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C5)cycloalkyl(C1-C4)alkyl, (C1-C3)alkoxy(C1-C3)alkoxy and (C1-C3)alkoxy(C1-C3)alkyl, each of which is optionally substituted with 1 to 4 groups independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, benzyloxycarbonyl, hydroxy(C1-C4)alkyl, protected hydroxy(C1-C4)alkyl, protected (C1-C4)alkylamino, cyano(C1-C4)alkyl, (C1-C4)alkylamino, di(C1-C4)alkylamino, halogen, cyano, oxo, protected hydroxy, protected amino, protected MeSO2NH(C1-C4)alkyl, protected H2NC(═O)CMe2(C1-C4)alkyl, protected H2NC(═O)CHMe(C1-C4)alkyl, protected H2NC(═O)CH2(C1-C4)alkyl, nitro, hydroxy, amino, MeSO2—, MeSO2N(Me)(C1-C4)alkyl, MeSO2NH(C1-C4)alkyl, H2NC(═O)CMe2(C1-C4)alkyl, H2NC(═O)CHMe(C1-C4)alkyl, H2NC(═O)CH2(C1-C4)alkyl, —OR, —NR2, —COOR, —CONR2, and —SOkR, wherein k is 0, 1 or 2, and wherein each R is independently —H, an alkyl group, a cycloalkyl group or an aryl group;
• A1 is (a) a bond, or (b) (C1-C3)alkylene, CH2CH2O, wherein the oxygen is attached to Cy1;
• Cy1 is aryl, heteroaryl, monocyclic cycloalkyl or monocyclic heterocyclyl, each of which is optionally substituted with 1 to 4 groups independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, benzyloxycarbonyl, hydroxy(C1-C4)alkyl, cyano(C1-C4)alkyl, (C1-C4)alkylamino, di(C1-C4)alkylamino, halogen, cyano, oxo, nitro, protected hydroxy, protected amino, hydroxy, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, protected CONH2, protected (C1-C4)alkylaminocarbonyl, amino, protected (C3-C4)cycloalkylaminocarbonyl, {(C1-C4)alkyl}{(C3-C4)cycloalkyl}aminocarbonyl, protected (C1-C4)alkylcarbonylamino, MeSO2—, MeSO2N(Me)(C1-C4)alkyl, MeSO2NH(C1-C4)alkyl, H2NC(═O)CMe2(C1-C4)alkyl, H2NC(═O)CHMe(C1-C4)alkyl, H2NC(═O)CH2(C1-C4)alkyl, —OR, —NR2, —COOR, —CONR2, and SOkR, wherein k is 0, 1 or 2, and wherein each R is independently —H, an alkyl group, a cycloalkyl group or an aryl group;
• A2 is (a) a bond, O, S or NR4, wherein R4 is (C1-C3)alkyl or (C3-C6)cycloalkyl;
• or (b) (C1-C3)alkylene or (C1-C2)alkoxy, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, and trifluoromethyl;
• Cy2 is (a) hydrogen or (b) aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted with 1 to 4 groups independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, benzyloxycarbonyl, hydroxy(C1-C4)alkyl, cyano(C1-C4)alkyl, (C1-C4)alkylamino, di(C1-C4)alkylamino, halogen, cyano, oxo, nitro, protected hydroxy, protected amino, hydroxy, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, protected CONH2, protected (C1-C4)alkylaminocarbonyl, amino, protected (C3-C4)cycloalkylaminocarbonyl, {(C1-C4)alkyl}{(C3-C4)cycloalkyl}aminocarbonyl, protected (C1-C4)alkylcarbonylamino, MeSO2—, MeSO2N(Me)(C1-C4)alkyl, MeSO2NH(C1-C4)alkyl, H2NC(═O)CMe2(C1-C4)alkyl, H2NC(═O)CHMe(C1-C4)alkyl, H2NC(═O)CH2(C1-C4)alkyl, —OR, —NR2, —COOR, —CONR2, and —SOkR, wherein k is 0, 1 or 2, and wherein each R is independently —H, an alkyl group, a cycloalkyl group or an aryl group;
• said method comprising the step of reacting a β-haloalcohol compound represented by the following structural formula:
• wherein X is a leaving group, with a isocyanate compound represented by the following structural formula:
• thereby forming the oxazinone compound.