Process for the preparation of isoindoline

Details Process for the preparation of isoindoline Process for the preparation of isoindoline

2001-02-16

2001-11-20

Shah, Mukund J. (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S482000

Reexamination Certificate

active

06320058

ABSTRACT:

BACKGROUND OF THE INVENTION
Isoindoline is a synthesis intermediate that is widely used, especially in the preparation of pharmaceutical active ingredients.
In particular, isoindoline is an important intermediate in the synthesis of 2-(S)-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid of formula (I):
its pharmaceutically acceptable salts and its hydrates.
The compound of formula (I), and its addition salts and hydrates, have especially valuable pharmacological properties. They are very powerful insulin secretors, which makes them useful in the treatment of non-insulin-dependent diabetes. The compound of formula (I), its preparation and its therapeutic use have been described in Patent Specification EP 0 507 534. Its industrial preparation is described in Patent Specification WO 99/01430. Given the pharmaceutical value of this compound, it was important to be able to obtain the intermediate isoindoline using a high-performance industrial synthesis process.
DESCRIPTION OF THE PRIOR ART
A number of methods for the preparation of isoindoline are already known. No process described in the literature, however, enables isoindoline to be obtained with satisfactory purity and yield, whilst still being readily transposable to an industrial scale and advantageous from the point of view of profitability.
The preparation of isoindoline by the electrolytic or chemical reduction of phthalimide is described in the journals Bull. Soc. Chim. France 1956, 906-910, J. Pharm. Sci. 1964, 53(8), 981 and J. Org. Chem. 1988, 53 (22), 5381-5383.
Those processes do not, however, enable isoindoline to be obtained in a yield of more than 50%.
The preparation of isoindoline by cyclising &agr;,&agr;′-dibromo-xylene in the presence of p-toluenesulphonylamine, followed by deprotection of the resulting N-(p-toluenesulphonyl)-isoindoline is described in the journals J. Org. Chem. 1957, 22 , 1255-6 and Org. Synth. Collect. Vol. V, 406-408 and 1064-1066.
That method, in addition to its low yield (less than 50%), has the disadvantage of using a highly lacrimogenic starting material.
Patent Specifications FR 1 577 845 and FR 1 578 582 describe the preparation of isoindoline by reacting &agr;,&agr;′-dichlorobenzene with hexamethylenetetraamine, followed by treatment of the resulting ammonium salt in an HCI or SO
2
medium, and then cyclisation of the resulting o-chloromethyl-benzyl amine compound in a basic medium.
That method is especially lengthy and does not enable isoindoline to be obtained with a satisfactory yield.
The journal Izvestia Eng. Ed. 1959, 1778-80, describes the synthesis of isoindoline by hydrogenation of phthalonitrile at 100-120 atm in a dioxane/ammonia mixture, in the presence of nickel or cobalt at 100° C.
That process has several disadvantages. It has not been possible to reproduce the stated yields (91 to 98%). After removal of the catalyst by filtration and removal of the solvent by distillation, it has not been possible to distill off any compound from the medium heated to 120° C. in vacuo at 20 mbars. Moreover, in the case of industrial-scale processing the presence of ammonia in the reaction mixture requires a special installation in order to protect the environment.
DETAILED DESCRIPTION OF THE INVENTION
Given the value of isoindoline as an intermediate in the synthesis of pharmaceutical active ingredients, especially 2-(S)-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)-butyric acid, and given the absence of a process that enables it to be obtained with a good yield and satisfactory purity, starting from inexpensive starting materials but avoiding the use of ammonia, the Applicant carried out in-depth research, which resulted in the development of a new process for the preparation of isoindoline.
This process enables isoindoline to be obtained in a single step, by simple catalytic hydrogenation of phthalonitrile, a commercial product, without the addition of ammonia, with a yield of more than 75% and with very good purity.
In order to obtain that result, the following operating conditions must be applied:
The catalyst used is 5% Pt/C. In fact, it became apparent, surprisingly, that of all the catalysts generally employed, only Pt/C enabled isoindoline to be obtained within a reasonable reaction time (Table 1).
The amount of Pt/C used is from 10 to 25%, preferably 20%, of the weight of the phthalonitrile.
TABLE 1
Catalyst
Hydrogenation time
% isoindoline
Pd/C
20 h
1
Raney Ni
20 h
0
Rh/C
20 h
0
Ru/C
20 h
0
Pt/C
 6 h
89.9
Reaction conditions: tetrahydrofuran, 20% by weight of catalyst, 60° C., 180 bars of hydrogen
The solvent used is tetrahydrofuran, a mixture of tetrahydrofuran/water in which the water content is less than 10%, preferably less than 5%, or dimethoxyethane. In fact, it became apparent, surprisingly, that only tetrahydrofuran (used on its own or in the presence of a limited amount of water) and dimethoxyethane enabled a satisfactory conversion rate to be obtained (Table 2).
TABLE 2
Solvent
Hydrogenation time
% isoindoline
tetrahydrofuran
 6 h
89.9
tetrahydrofuran/water 98/2
 6 h
89.3
dimethoxyethane
 9 h
86.2
dioxane
20 h
40
ethanol
20 h
49
dimethylformamide
20 h
0
Reaction conditions: catalyst Pt/C (20% by weight), 60° C., 180 bars of hydrogen
The hydrogen pressure inside the reactor is from 100 to 180 bars and preferably from 150 to 180 bars.
The temperature of the reaction mixture is from 30 to 100° C. and preferably from 50 to 70° C.
The isoindoline obtained under those conditions can then readily be isolated from its reaction medium by distillation, and then purified by precipitation in the form of a hydrochloride from a solvent, such as, for example, ethanol or ethyl acetate.
The isoindoline hydrochloride so obtained has very good purity and contains, for example, less than 1.5%, preferably less than 0.2%, of 2-methylbenzylamine, which makes its use especially advantageous in the synthesis of active ingredients, such as the compound of formula (I).
By way of illustration, enantioselective reduction by catalytic hydrogenation of the isoindoline obtained according to the process of the invention enables cis-perhydroisoindole to be obtained with highly satisfactory purity and yield. That compound, when reacted with the anhydride of formula (II):
yields the compound of formula (III):
the catalytic hydrogenation of which in the presence of an asymmetric catalyst yields the compound of formula (I).


REFERENCES:
patent: 2773902 (1956-12-01), Heaton et al.
L. Kh. Freidlin et al., Formation of nitrogenous heterocycles in catalytic hydrogenation of dinitriles of succinic and phthalic acids. Izvest. Akad. Nauk S.S.S.R. Otdel. Khim. Nauk., 1959, pp. 1859-1862.*
P.N. Rylander, Catalytic Hydrogenation in Organic Syntheses, 1979, pp. 140-142; ISBN 0-12-605355-3.

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