Process

Details Process Process

1992-10-14

1994-08-09

Daus, Donald G.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

560 18, 560254, C07D20934

Patent

active

053367812

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to an improved process for the preparation of substituted indolone derivatives. Such compounds are in particular described in EP-0113964-B as being useful in cardiovascular therapy, and in EP-299602-A as agents useful in the treatment of Parkinson's disease.
Processes for the preparation of substituted indolone derivatives have been described in the art, for example in EP-113964-B, and in EP-300614-A1. In particular, EP-300614-A1 describes a series of steps which allow preparation of compounds of the structure ##STR3## in which R is, inter alia, hydrogen or C.sub.1-4 alkyl and n is 1 to 3, the final step of which comprises displacement by an amine of a halogen leaving group, from the precursor compounds of structure ##STR4## in which X is halogen.
The present invention provides an improvement to the reaction sequence disclosed in EP-300614-A1 and provides, in a first aspect, a process for the preparation of a compound of structure (I) ##STR5## in which n is 1 to 3 and each group R is hydrogen or C.sub.1-4 alkyl, which comprises, reaction of a compound of structure (II) ##STR6## in which n is 1 to 3 and R.sup.1 is C.sub.1-4 alkyl, phenyl or substituted phenyl with an amine of structure HNR.sub.2 where R is as described for structure (I), and optionally thereafter forming a salt.
Suitably, one of the groups R is hydrogen and the other is hydrogen or C.sub.1-4 alkyl; preferably, both groups R are C.sub.1-4 alkyl, in particular propyl. Suitably n is 1 to 3; preferably n is 2.
Suitably R.sup.1 is C.sub.1-4 alkyl such as methyl, phenyl or substituted phenyl, for example p-methylphenyl; preferably R.sup.1 is p-methylphenyl.
Suitably, the reaction is carried out in a variety of solvents at elevated temperature, preferably in water, at a temperature of between about 80.degree. and about 90.degree. C.
The compounds of structure (II) are novel and themselves form a further aspect of the invention.
Surprisingly, it has been found that the reaction described herein provides the desired product in much higher yields than previously obtained using the prior art process described in EP-300614-A in which a halogen leaving group is displaced by an amine.
More particularly, it has been found that, for example when used to prepare the compound 4-[2-(di-n-propylamino)ethyl]-1,3-dihydro-2H-indol-2-one hydrochloride salt ((I), n=2, R=n-propyl), from the corresponding precursor (II) in which the leaving group is bromine (rather than OSO.sub.2 R.sup.1), isolated yields of about 60% are obtained, whereas yields of up to 87% have been obtained from compounds of structure (II) in which an oxygen leaving group is present.
This significant increase in yield could not have been predicted from the prior art disclosure of EP-300614-A or from general prior art knowledge.
As referred to above, the method is particularly useful for the preparation of the compound 4-[2-(di-n-propylamino)ethyl]-1,3-dihydro-2H-indol-2-one hydrochloride salt (INN:ropinirole), a compound useful for the treatment of Parkinson's disease (EP-299-602-A). In addition, when used to prepare the compounds of the invention (and in particular ropinirole) the processes used to prepare the compounds (II), proceed via important intermediates which themselves form a further aspect of the invention. In particular, the compounds (II) can be prepared via the following route: ##STR7## (a) R.sup.2 COCl, ZnCl.sub.2, CH.sub.2 Cl.sub.2 -10.degree.-0.degree.; C.sub.6 H.sub.12 N.sub.4, IMS, .DELTA.; 50% aq. AcOH, .DELTA.; Na.sub.2 S.sub.2 O.sub.5, IMS, H.sub.2 O, CH.sub.2 Cl.sub.2, NaHCO.sub.3, 5.degree.-12.degree. C.;
In the above-noted scheme, R.sup.1 and n are as described for formula (II) and R.sup.2 can be for example, C.sub.1-4 alkyl, in particular methyl, phenyl or substituted phenyl. Starting compounds (C), are known or can be prepared by standard methods. For example, when used to prepare the preferred compounds of structure (II) in which n is 2, the starting material (C) in which n is 2, i.e. isochroman, is commercially available.
In a further asp

REFERENCES:
patent: 3574232 (1971-04-01), Canas-Rodruigez
patent: 4588790 (1986-05-01), Gallagher
patent: 4593033 (1986-06-01), Hartmann
patent: 4629733 (1986-12-01), Muller et al.
patent: 5010079 (1991-04-01), Manoury
Sagami, Chem. Abstr. vol. 90 Entry 103933u (1978).

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