Process for the preparation of cell proliferation inhibitors

Details Process for the preparation of cell proliferation inhibitors Process for the preparation of cell proliferation inhibitors

2001-09-20

2004-03-23

O'Sullivan, Peter (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S503000

Reexamination Certificate

active

06710185

ABSTRACT:

TECHNICAL FIELD
The instant invention is directed to a process for the preparation of cell proliferation inhibitors and to intermediates useful in the process.
BACKGROUND OF THE INVENTION
Microtubules play a key role in the regulation of cell architecture, metabolism, and division. The microtubule system of eucaryotic cells comprises a dynamic assembly and disassembly matrix in which heterodimers of tubulin polymerize to form microtubules in both normal and neoplastic cells. Within neoplastic cells, tubulin is polymerized into microtubules which form the mitotic spindle. The microtubules are then depolymerized when the mitotic spindle's use has been fulfilled. Agents which disrupt the polymerization or depolymerization of microtubules in neoplastic cells, thereby inhibiting the proliferation of these cells, comprise some of the most effective cancer chemotherapeutic agents in use.
While commonly owned U.S. Patent Provisional Application Ser. No. 60/136,542 teaches the preparation of substituted indole cell proliferation inhibitors, the synthesis is not amenable to large-scale preparation. For example, the sulfonylation of N-formylindoline is accomplished using five equivalents of chlorosulfonic acid. Upon workup, the excess chlorosulfonic acid is quenched, causing a vigorous reaction. When conducted on large amounts of material, this procedure becomes hazardous, rendering these conditions impractical for large-scale synthesis. In addition, the oxidation of the indolinesulfonamide to the corresponding indolesulfonamide is accomplished with salcomine in the presence of oxygen. The yield on this reaction is extremely low and the results are often not reproducable, making the procedure inefficient and thus impractical for large-scale synthesis.
As shown by the above examples, there is still a need in the pharmaceutical manufacturing industry for the efficient preparation of substituted indole cell proliferation inhibitors. The instant invention discloses a synthesis of cell proliferation inhibitors which offers higher overall yields and less hazardous conditions, making it amenable to large-scale preparation.
SUMMARY OF THE INVENTION
In one embodiment of the instant invention, therefore, is disclosed a process for preparing a compound of formula (5)
or a therapeutically acceptable salt thereof, wherein
R
1
and R
5
are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; and
R
2
, R
3
, and R
4
are independently selected from the group consisting of alkyl and alkoxy;
the process comprising:
(a) reacting N-formylindoline with chlorosulfonic acid and thionyl chloride; and
(b) reacting the product from step (a) with a base and a compound of formula (4) (4).
In a preferred embodiment of the instant invention is disclosed a process for preparing a compound of formula (5), or a therapeutically acceptable salt thereof, the process comprising:
(a) reacting N-formylindoline with chlorosulfonic acid and thionyl chloride at about 65° C. to about 85° C. for about 1 to about 5 hours; and
(b) reacting the product from step (a) with a carbonate salt and a compound of formula (4).
In a more preferred embodiment the compound of formula (5) is 1-formyl-N-(3,4,5-trimethoxyphenyl)-5-indolinesulfonamide.
In another embodiment of the instant invention is disclosed a process for reacting indoline with an N-formylating reagent to provide the N-formylindoline.
In another embodiment of the instant invention is disclosed a process for preparing a compound of formula (7)
the process comprising:
(a) reacting the compound of formula (5) with a reducing agent; and
(b) reacting the product of step (a) with an oxidizing agent.
In a preferred embodiment of the instant invention is disclosed a process for preparing a compound of formula (7),
the process comprising:
(a) reacting a compound of formula (5) with a reducing agent at about −5° C. to about 30° C. for about 1 to about 5 hours; and
(b) reacting the product of step (a) with an oxidizing agent at about −5° C. to about 35° C. for about 2 to about 14 hours.
In a more preferred embodiment the compound of formula (7) is 1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide.
In yet a further embodiment of the instant invention is disclosed a process for preparing a compound of formula (7), the process comprising:
(a) reacting the compound of formula (5) with a deformylating agent;
(b) reacting the product from step (a) with an oxidizing agent; and
(c) reacting the product from step (b) with a base and a methylating agent.
In yet an additional embodiment of the instant invention is disclosed a process for preparing a compound of formula (7a)
the process comprising:
(a) reacting indoline with a formylating agent;
(b) reacting the product of step (a) with chlorosulfonic acid and thionyl chloride;
(c) reacting the product of step (b) with a base and a compound of formula (4);
(d) reacting the product of step (c) with a reducing agent; and
(e) reacting the product of step (d) with an oxidizing agent.
In another embodiment of this aspect of the instant invention disclosed is a process for preparing a compound of formula (7a),
the process comprising:
(a) reacting indoline with a formylating agent;
(b) reacting the product of step (a) with chlorosulfonic acid and thionyl chloride;
(c) reacting the product of step (b) with a base and a compound of formula (4);
(d) reacting the product of step (c) with a deformylating agent;
(e) reacting the product of step (d) with an oxidizing agent; and
(f) reacting the product of step (e) with a base and a methylating agent.
In a further embodiment of the instant invention is disclosed a process for preparing a compound of formula (10a)
the process comprising:
reacting a compound of formula (7a) with N,N-dimethylaminoacetyl chloride hydrochloride in the presence of N,N-dimethylaminopyridine and diisopropylethylamine.
In another embodiment of the instant is disclosed a compound of formula (I)
or a therapeutically acceptable salt thereof, wherein
R
1
, R
2
, R
3
, R
4
, and R
5
are previously defined; and
R
A
is selected from the group consisting of hydrogen, formyl, and methyl.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention is directed to processes for the preparation of cell proliferation inhibitors and to intermediates which are useful in these processes of preparation. As used in the instant specification the following terms have the meanings specified.
The term “alkoxy,” as used herein, represents an alkyl group attached to the parent molecular moiety through an oxygen atom.
The term “alkyl,” as used herein, represents a monovalent group of one to six carbon atoms derived from a straight or branched chain saturated hydrocarbon.
The term “base,” as used herein, represents a reagent capable of accepting protons during the course of a reaction. Examples of bases include carbonate salts such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, and cesium carbonate; halides such as cesium fluoride; phosphates such as potassium phosphate, potassium dihydrogen phosphate, and potassium hydrogen phosphate; hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; disilylamides such as lithium hexamethyldisilazide, potassium hexamethyldisilazide, and sodium hexamethyldisilazide; trialkylamines such as triethylamine, diisopropylamine, and diisopropylethylamine; heterocyclic amines such as imidazole, pyridine, pyridazine, pyrimidine, and pyrazine; bicyclic amines such as DBN and DBU; and hydrides such as lithium hydride, sodium hydride, and potassium hydride. The base chosen for a particular conversion depends on the nature of the starting materials, the solvent or solvents in which the reaction is conducted, and the temperature at which the reaction is conducted.
The term “deformylating agent,” as used herein, represents a reagent capable of removing a formyl group from the nitrogen atom of a molecule during the course of a reaction. Examples of deformylating agents include a mixture of hydrogen fluoride, anisole, an

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