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US 5,665,877 AGranted
Synthesis of bisindolylmaleimides
AssigneeEli Lilly and Company
InventorsMargaret M. Faul, Michael R. Jirousek, Leonard L. Winneroski, II
Life of this patent
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Abstract
The present invention provides a novel synthesis of the compounds of Formula (I): ##STR1## The compounds are produced in high yield and without utilizing expensive chromatographic separations. The synthesis is particularly advantageous because it is stereoselective.
Claims6
A process which comprises
- (a) Alkylating a compound of Formula (III):
- ##STR19## wherein, R.sup.2 is --O-triphenylmethyl or --O-methoxytriphenylmethyl;
- Z is --(CH.sub.2).sub.n --;
- and n is independently 1, 2, or 3 with a lithium acetylide, a cerium acetylide, or organometalic reagent selected from vinyl cuprate, vinyl aluminum, vinyl tin, vinyl lithium, or vinyl Grignard;
- to produce a compound of the Formula (IV):
- ##STR20## (b) Reacting a compound of the Formula (IV) with a compound of the Formula:
- ##STR21## wherein R.sup.3 is halo, a protected hydroxy, or combines with the adjacent carbon to form an olefin;
- R.sup.4 is chloro, bromo, or iodo;
- and n is independently 1,2, or 3;
- to form a compound of the Formula (V):
- ##STR22## (c) Converting the compound of the Formula (V) to a compound of the Formula (II):
- ##STR23## wherein:
- L.sup.1 is independently a leaving group;
- and
- (d) Alkylating a compound of Formula (VIII):
- ##STR24## wherein R is independently hydrogen, halo, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, haloalkyl, nitro, NR.sup.5 R.sup.6, or --NHCO(C.sub.1 -C.sub.4 alkyl), R.sup.5 and R.sup.6 are independently hydrogen, metal, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 membered ring, and m is independently 0, 1, 2, or 3, with a compound of Formula II, to produce a compound of the formula:
- ##STR25##
14 more elements
A process which comprises
- Alkylating a compound of Formula (IIIs):
- ##STR26## wherein, R.sup.2 is --O-triphenylmethyl or --O-methoxytriphenylmethyl;
- Z is --(CH.sub.2).sub.n --;
- and n is independently 1, 2, or 3 with a lithium acetylide, a cerium acetylide, or organometalic reagent selected from vinyl cuprate, vinyl aluminum, vinyl tin, vinyl lithium, or vinyl Grignard;
- to produce a compound of the Formula (IVs):
- ##STR27## (b) Reacting a compound of the Formula (IVs) with a compound of the Formula:
- ##STR28## wherein R.sup.3 is halo, a protected hydroxy, or combines with the adjacent carbon to form an olefin;
- R.sup.4 is chloro, bromo, or iodo;
- and n is independently 1,2, or 3;
- to form a compound of the Formula (Vs):
- ##STR29## (c) Converting the compound of the Formula (Vs) to a compound of the Formula (IIs):
- ##STR30## wherein L.sup.1 is independently a leaving group;
- and (d) Alkylating a compound of Formula (VIII):
- ##STR31## wherein R is independently hydrogen, halo, C.sub.1 -C.sub.4 alkyl , hydroxy, C.sub.1 -C.sub.4 alkoxy, haloalkyl, nitro, NR.sup.5 R.sup.6, or --NHCO(C.sub.1 -C.sub.4 alkyl);
- R.sup.5 and R.sup.6 are independently hydrogen, methyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 membered ring;
- m is independently 0, 1, 2, or 3;
- with a compound of Formula IIs, to produce a compound of the formula:
- ##STR32##
15 more elements
A process which comprises
- (a) Alkylating a compound of Formula (IIIr):
- ##STR33## wherein R.sup.2 is --O-triphenylmethyl or --O-methoxytriphenylmethyl;
- Z is --(CH.sub.2).sub.n --;
- and n is independently 1, 2, or 3 with a lithium acetylide, a cerium acetylide, or organometalic reagent selected from vinyl cuprate, vinyl aluminum, vinyl tin, vinyl lithium, or vinyl Grignard;
- to produce a compound of the Formula (IVr):
- ##STR34## (b) Reacting a compound of the Formula (IVr) with a compound of the Formula:
- ##STR35## wherein R.sup.3 is halo, a protected hydroxy, or combines with the adjacent carbon to form an olefin;
- R.sup.4 is chloro, bromo, or iodo;
- and n is independently 1,2, or 3;
- to form a compound of the Formula (Vr) ##STR36## (c) Converting the compound of the Formula (Vr) to a compound of the Formula (IIr):
- ##STR37## wherein L.sup.1 is independently a leaving group;
- and
- (d) Alkylating a compound of Formula (VIII):
- ##STR38## wherein R is independently hydrogen, halo, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, haloalkyl, nitro, NR.sup.5 R.sup.6, or --NHCO(C.sub.1 -C.sub.4 alkyl);
- R.sup.5 and R.sup.6 are independently hydrogen, methyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 membered ring;
- m is independently 0, 1, 2, or 3;
- with a compound of Formula IIr, to produce a compound of the formula:
- ##STR39##
15 more elements
Dependencies are inferred from the claim text.