Method for preparing a substituted perhydroisoindole

Details Method for preparing a substituted perhydroisoindole Method for preparing a substituted perhydroisoindole

2000-03-20

2000-10-17

Stockton, Laura L.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D20944

Patent

active

061334545

DESCRIPTION:

BRIEF SUMMARY
The present application is a U.S. National Application filed under 35 USC 371 of PCT/FR98/01405, filed Jul. 1, 1998, based upon French Application Serial No. 97.08431, filed Jul. 3, 1997.
The present invention relates to a process for the industrial synthesis of a substituted perhydroisoindole of formula (I): ##STR2## and of pharmaceutically acceptable salts thereof.
The compound of formula (I) and its addition salts have especially valuable pharmacological properties. It is a very powerful secretor of insulin, which makes it useful in the treatment of non-insulin-dependent diabetes.
The compound of formula (I), its preparation and its use therapeutically have been described in European Patent Specification EP 0 507 534. The industrial preparation of a compound such as the compound of formula (I), however, requires an in-depth investigation of all the reaction steps, of the selection of starting materials, and of the reagents and solvents that make it possible to obtain optimum yields.
The process for the synthesis of the compound of formula (I) described in Patent Specification EP 0 507 534 does not enable the compound to be obtained with an optimum yield. In fact, obtaining the isomer of interest by the synthesis method described does not enable the desired regioselectivity to be obtained. It is thus necessary to carry out a number of purification operations in order to obtain the "pharmaceutical grade" isomer.
Given the pharmaceutical value of the compound and given the absence of a process that enables it to be obtained with a good yield, with satisfactory purity and, if possible, starting from inexpensive starting materials that are commercially available, more in-depth investigation has been carried out and has resulted in the development of a new especially valuable synthesis process.
The invention relates more specifically to a process for the preparation of the compound of formula (I), characterised in that dimethyl succinate is reacted with benzaldehyde in methanolic medium, to yield the diacid of formula (II): ##STR3## which, after heating in an aprotic solvent, such as tetrahydrofuran or isopropyl ether, in the presence of acetic anhydride, yields the anhydride of formula (III): ##STR4## which is reacted with the perhydroisoindole of formula (IV) in an aprotic solvent, such as toluene, acetonitrile, ethyl acetate, methyl tert-butyl ether or tetrahydrofuran, or in a tetrahydrofuran/toluene mixture, ##STR5## to yield the compound of formula (V): ##STR6## which is subjected to catalytic hydrogenation using as asymmetric hydrogenation catalyst the complex rhodium/(2S,4S)-N-butoxycarbonyl-4-diphenylphosphino-2-diphenylphosphino-m etlhylpyrrolidine or Rh/(S,S) BPPM, in methanolic or methylene chloride medium, followed by conversion to a salt in the presence of an amine A to yield a compound of formula (VI): ##STR7## which in a basic medium in the presence of a mineral salt yields an addition salt of the compound of formula (I), which is converted, if desired, into the corresponding acid, or, if desired, into a pharmaceutically acceptable addition salt.
Amongst the pharmaceutically acceptable addition salts, there may be mentioned by way of non-limiting example the sodium and calcium salts in hydrated or non-hydrated form.
The preferred addition salt is the calcium salt.
The process is especially valuable for the following reasons: of formula (IV) allows very great regioselectivity to be obtained. In fact, the compound of formula (V) is isolated with a regioselectivity of more than 99.5%. complex Rh/(S,S)BPPM provides an enantiomeric excess of more than 92%. The molar ratio of complex/substrate used in this Step is from 1/2000 to 1/10000 and preferably from 1/2000 to 1/4000.
The rhodium complex Rh/(S,S)BPPM is known from the literature to be an enantiospecific hydrogenation catalyst.
However, in methanol or methylene chloride (reaction solvents), the acid of formula (I/a) has a tendency to evolve to a mixture of regloisomers (I/a)/(I/b): ##STR8##
A kinetic study has made it possible to show that the p

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