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Process for the preparation of indolinone compound

IP.com Disclosure Number: IPCOM000241006D
Publication Date: 2015-Mar-18
Document File: 2 page(s) / 212K

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The IP.com Prior Art Database

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Page 01 of 2

Process for the preparation of indolinone compound

    Described hereinafter is a process for the coupling of N-[(4-methyl-piperazin- 1-yl)-methylcarbonyl]-N-methyl-p-phenylenediamine and 1-acetyl-3-(1-methoxy-1- phenylmethylene)-6-methoxycarbonyl-2-indolinone.

The coupling can be done in the presence of an organic solvent as reported in US 6,762,180, e.g. dimethylformamide, toluene, acetonitrile, THF, DMSO, DCM. Alternative solvents such as MeOH, iPrOH, MeTHF, 1,3-dioxolane and NMP can be used. Under these conditions the acetyl group of the indolinone moiety can be removed in situ. To complete the acetyl group removal, a base can be added, such as inorganic bases (like lithium hydroxide, sodium hydroxide, potassium hydroxide etc.); or organic bases (like sodium methoxide or amines like butylamine, dimethylamine, piperidine etc.).

The above reaction is performed in yield of up to 95%.

Two typical by products were identified:

Compound A: (3Z)-2,3-dihydro-3-[[[4-[methyl[2-(4,4-dimethyl-1-piperazinium)

acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo-1H-indole-6-carboxylic acid

methyl ester

HN

O

N+

N

O

N

O

NH

O

Compound B: methyl 1-acetyl-3-(hydroxy(phenyl)methylene)-2-oxoindoline-6-

carboxylate

N

HO O

O

O

OMe


Page 02 of 2

    The level of the above impurities can be significantly lowered performing the reaction in certain solvents such as MeOH, iProH, THF and MeTHF (less than 1%) as compared to the amounts obtained for example in DMF or NMP (around 4-6%).

Example:

    A mixtu...