Synthesis of indolymaleimides

• US 6,037,475 A
• Filed: 02/11/1999
• Issued: 03/14/2000
• Est. Priority Date: 03/20/1996
• Status: Expired due to Fees

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Faul, Margaret M., McDonald, John H. III, Neel, David Andrew, Jirousek, Michael R.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Rao, Deepak R.
• Application Number:
  US09/248,263
• Time in Patent Office: 397 Days
• Field of Search: 548/466, 548/548, 548/549
• US Class Current: 548/466
• CPC Class Codes: C07D 209/18 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/24 with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings

Abstract

The present invention provides a method for synthesizing indolylmaleimides by reacting an activated maleimide preferably with an optionally substituted organometalic-3-indole in the presence of a transition metal catalyst.

Claims

1. A method of making an optionally substituted 4-(indol-3-yl)-3-hydroxy pyrrole-2,5-dione which comprises reacting an optionally substituted, N-protected indol-3-yl-acetamide with an alkyl oxalate and a strong organic base in a polar aprotic solvent.

2. The method of claim 1, wherein said optionally substituted, N-protected indol-3-yl acetamide has the formula:

##STR34## wherein R³ is selected from hydrogen and a protecting group,

R⁷ '"'"'s are hydrogen or up to four optional substituents independently selected from halo, alkyl, hydroxy, alkoxy, haloalkyl, nitro, --NHCO(alkyl), and --NR⁹ R¹⁰ where R⁹ and R¹⁰ are independently hydrogen or methyl, and

R⁸ is hydrogen or an optional substituent selected from an alkyl, haloalkyl, alkenyl, arylalkyl, alkoxyalkyl, hydroxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, acyloxyalkyl, cyanoalkyl, amidinoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, alkylaryl, aminoalkyl, heteroaryl, carbonylalkyl, amidinothioalkyl, nitroguanidinoalkyl, a protecting group;

an alkylglycose residue, a group of the formulae;

##STR35## where;

Het signifies a heterocyclyl group,

W signifies NH, S or a bond,

T signifies NH or S,

V signifies O, S, NH, or NCN,

A signifies alkylthio, amino, monoalkylamino or dialkylamino,

Ar signifies aryl,

R¹⁶ is hydrogen, alkyl, haloalkyl, acetyl, aryl, --CH(aryl)₂, amino, monoalkylamino, dialkylamino, guanidino, --C(═

N(alkoxycarbonyl))--NH--(alkoxycarbonyl), amidino, hydroxy, carboxy, alkoxycarbonyl or heterocyclyl;

R¹⁴ is hydrogen or an optionally substituted alkyl;

or R⁸ and R¹⁴ are lined together through a group of the formula;

space="preserve" listing-type="equation">[--(CH.sub.2).sub.r --X--(CH.sub.2)--]

where X is ##STR36## where R¹⁷ and R¹⁸ are independently hydroxy, carboxy, acyloxy, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkoxycarbonyl, cyano, amidino or aminocarbonyl, and

n is 1, 2, 3, 4, 5, or 6, p and q are independently 1, 2, 3, or 4, r is 1, 2, or 3, s is 0, 1, 2, or 3, t is 1 or 2, and u is 0 or 1.

3. A method for preparing an activated maleimide from an optionally substituted 4-(indol-3-yl)-3-hydroxy pyrrole-2,5-dione which comprises reacting said optionally substituted 4-(indol-3-yl)-3-hydroxy pyrrole-2,5-dione in an inert solvent with a compound selected from trifluoromethanesulfonic anhydride and an oxalyl halide.