One pot synthesis of 2-oxazolidinone derivatives

Details One pot synthesis of 2-oxazolidinone derivatives One pot synthesis of 2-oxazolidinone derivatives

1998-05-13

2000-07-04

Shah, Mukund J.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D26304, C07D26316

Patent

active

060841036

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to an improved process for preparing substituted indole derivatives which are useful for the treatment and prophylaxis of migraine. More particularly, the present invention provides an improved process for the preparation of the 5HT.sub.1 -like receptor agonist (S)-4-{[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl}-2-oxazolidinone, which is known to be effective for the treatment of migralne.
Selective 5-HT.sub.1 -like receptor agonists are known to be useful therapeutic agents. The 5-HT.sub.1 -like receptor mediates vasoconstriction and thus modifies blood flow in the carotid vascular bed. European patent specification 0313397 describes a class of specific 5-HT.sub.1 -like receptor agonists which are beneficial in the treatment or prophylaxis of conditions wherein vasoconstriction in the carotid vascular bed is indicated, for example, migraine, a condition associated with excessive dilation of the carotid vasculature.
International patent specification WO91/18897 describes a further class of compounds having exceptional "5-HT1-like" receptor agonism and excellent absorption following oral dosing. These properties render the compounds disclosed in WO91/18897 particularly useful for certain medical applications, notably the prophylaxis and treatment of migraine, cluster headache and headache associated with vascular disorders, hereinafter referred to collectively as "migraine". One particularly preferred compound described in WO91/18897 is (S)-N,N-dimethyl-2-[5-2oxo-1,3-oxazolidin-4-yl-methyl)-1H-indol-3-yl]ethyl amine which is also known as (S)-4-{[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl}-2-oxazolidinone and can be represented by formula (I): ##STR1##
The compound of formula (I) can exist as its (S) or (R) enantiomer and is specifically exemplified in WO91/18897. A number of possible routes for preparing the compound of formula (I) are suggested in WO91/18897.
A new process for preparing the compound of formula (I) has now been discovered. This process is advantageous over the processes disclosed in WO91/18897 in that it allows the final product to be made at a high yield on a large scale and in pure form by using a one pot procedure, thus avoiding the need for time-consuming and costly isolation of intermediates. The new process also avoids the need for dangerous reagents such as phosgene or environmentally hazardous reagents such as tin chloride.
According to the first aspect of the present invention, therefore, there is provided a process for the preparation of a (S)-4-{[3-[2(dimethylamino)ethyl]-1H-indol-5-yl]methyl}-2-oxazolidinone which process comprises the steps of hydrochloride, represented by formula (II) ##STR2## by adding sodium carbonate or sodium hydrogen carbonate and n-butyl chloroformate and reacting to give methyl(S)-N-butoxycarbonyl4-nitrophenylalaninate, represented by formula (III) ##STR3## b) reducing the compound of formula (III) to give methyl (S)-N-butoxycarbonyl4-amino phenylalaninate, represented by formula (IV) ##STR4## c) reducing the methyl ester grouping --CO.sub.2 CH.sub.3 in the compound of formula (IV) to give (S)-N-butoxycarbonyl-4-aminophenylalaninol, represented by formula (V) ##STR5## d) a ring closure of the compound of formula (V) to give (S)-4-(4-aminobenzyl)-2-oxazolidinone, represented by formula (VI) ##STR6## e) preparation of the diazonium salt of the compound of formula (VI) followed by reduction to give the hydrazine (S)-4-4-hydrazinobenzyl)-2-oxazolidinone hydrochloride, represented by formula (VII) ##STR7## f) Fischer reaction of the compound of formula (VII) to give the compound of formula (I)
Suitably, one or more of steps a) to f) are carried out using a one pot procedure. Preferably steps a) to d) are carried out by a one pot procedure followed by isolation of the compound of formula (VI) and then a second one pot procedure for steps e) and f).
Step a) is conveniently carried out in the presence of a solvent e.g. aqueous ethyl acetate or dioxane. Aqueous ethyl acetate is preferred. Sodium carbonate is used in prefe

REFERENCES:
patent: 5399574 (1995-03-01), Robertson et al.
patent: 5466699 (1995-11-01), Robertson et al.

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