Patent EA-001392-B1 (EA)
Title: Synthesis of bisindolylmalimides
Inventor: FAUL MARGARET MARY
IPC: C07D405/14
Filed: 1997-08-22
Abstract: 1. A process of preparing compounds of Formula I   wherein: R1 and R2 independently are optionally substituted 3-indolyl, which comprises, reacting an optionally substituted indole-3-acetamide of the formula   with optionally substituted indolyl-3-glyoxyl reagent of the formula   wherein: R3 is I, Cl, Br,or OR4; R4 is C1-C4-alkyl; and R11 is CH3 or H; in the presence of a base sufficiently strong to deprotonate the amide and methylene at the C-3 position of the indolyl-3-acetamide. 2. A process of preparing compounds of formula Ia   wherein: R1 and R2 independently are optionally substituted 3-indolyl, which comprises, reacting an optionally substituted indole-3-acetamide of the formula   with optionally substituted indolyl-3-glyoxyl reagent of the formula   wherein: R3 is I, Cl, Br,or OR<4>; and R4 is C1-C4-alkyl; in the presence of a base sufficiently strong to deprotonate the amide and methylene at the C-3 position of the indolyl-3-acetamide. 3. The process of claim 2, wherein optionally substituted indolyl-3-acetamide is a compound of the formula II   wherein: R<7> is hydrogen, alkyl, haloalkyl, arylalkyl, C1-C4-alkoxyalkyl, optionally protected hydroxyalkyl, optionally protected aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, or COO(C1-C4-alkyl); R8 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, (CH2)m-hydroxy, acetyl, carboxy, halo, haloalkyl, nitro, and (CH2)mNR5R6; wherein m is 0, 1, 2, or 3; and R5 and R6 are independently hydrogen, C1-C4-alkyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5- or 6- member ring. 4. The process of claim 2, wherein optionally substituted indolyl-3-acetamide is a compound of the formula (IIa)   wherein X is an optionally substituted C1-C4-alkylene. 5. The process of claim 3, wherein the optionally substituted indolylglycoxyl reagent is a compound of the formula (III)   wherein: R3 is I, Cl, Br,or OR4; R4 is C1-C4-alkyl; R7' is hydrogen, alkyl, haloalkyl, arylalkyl, alkoxyalkyl, optionally protected hydroxyalkyl, optionally protected aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, or trialkylaminoalkyl or COO(C1-C4-alkyl); R8 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, (CH2)m-hydroxy, acetyl, carboxy, halo, haloalkyl, nitro, and (CH2)mNR5R6; and m is 0, 1, 2, or 3. 6. The process of claim 2, wherein the optionally substituted indolyl-3-acetamide and optionally substituted glycoxyl reagent together form a compound of the formula (IV)   wherein W represents a C4-C8 optionally substituted alkylene moiety, and optionally having an internal ether (-O-), amino- (-NH-) or amide (-CONH-) linkage. 7. The process of claim 6, wherein the compound is   wherein Z is -(CH2)p-; R9 is halo, protected hydroxy, protected amino, NR5R6, NH(CF3), or N(CH3)(CF3); R5 and R6 are independently H or C1-C4-alkyl; wherein p is 0, 1, or 2; and m is independently 2 or 3. 8. The process of claim 2, wherein the indolyl-3-acetamide is a compound of the formula   wherein Z is -(CH2)p-; R9 is halo, protected hydroxy, protected amino group, NR5R6, NH(CF3), or N(CH3)(CF3); R5 and R6 are independently H or C1-C4-alkyl; p is 0, 1, or 2; and m is independently 2 or 3; R10 is a leaving group, hydroxy, or protected hydroxy group; and indolyl-3-glycoxyl reagent is of the formula   9. The process of claim 2, wherein the indolyl-3-acetamide is of the formula   and the indolyl-3-glycoxyl reagent is of the formula   10. The process of any one of claims 1-9, wherein the base is selected from the group consisting of alkali metal alkoxides, sodium hydride, lithium diisopropylamide, or n-butyllithium. 11. The process of claim 10, wherein R3 is OR4. 12. The process of claim 11, wherein the base is sodium hydride.