One pot synthesis of 2-oxazolidinone derivatives

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

1999-02-05

2001-10-16

Lambkin, Deborah C. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C560S022000

Reexamination Certificate

active

06303791

ABSTRACT:

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 5HT
1
-like receptor agonists other than (S)-4-{[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl}-2-oxazolidinone, which have a substituted indole ring structure.
Selective 5-HT
1
-like receptor agonists are known to be useful therapeutic agents. The 5-HT
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
1
-like receptor agonists which are beneficial in the treatment or prophylaxis of conditions herein 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-HT
1
-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”.
A further class of compounds which demonstrate improved metabolic stability and the necessary 5HT, receptor agonism, and also display a potentially selective inhibition of neurogenic inflammation and the nerve pathways responsible for the transmission of head pain are disclosed in pending International patent application no. PCT/GB95/00142. A particularly preferred compound of International application no. PCT/GB95/00142 is 4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)-oxazolidin-2-one.
Thus, International patent specification WO01/18897 and pending International patent application no. PCT/GB95/00142 disclose compounds of formula (I)
wherein
R
1
and R
2
are each independently hydrogen or C
1-4
alkyl or R
1
and R
2
are linked to form an azetidine ring; and
A is C
3-6
cycloalkyl, C
1-3
alkyl—C
3-6
cycloalkyl or C
2
-alkyl; provided that when R
1
and R
2
are both methyl, A is not C
2
-alkyl.
Compounds of formula (I) are 5HT
1
-like receptor agonists which are useful in the treatment and prophylaxis of migraine. A new process for preparing compounds of formula (I) has now been discovered.
The process is advantageous over the processes disclosed in WO91/18897 and PCT/GB95/00142 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 compound of formula (I) as hereinbefore defined, which process comprises the steps of
a) forming a carbamate from methyl 4-nitro-(L)-phenylalaninate hydrochloride, represented by formula (II)
by adding sodium carbonate or sodium hydrogen carbonate and n-butyl chloroformate and reacting to five methyl(S)-N-butoxycarbonyl-4-nitrophenylalaninate, represented by formula (III)
b) reducing the compound of formula (III) to give methyl (S)-N-butoxycarbonyl-4-amino phenylalaninate, represented by formula (IV)
c) reducing the methyl ester grouping —CO
2
CH
3
in the compound of formula (IV) to give (S)-N-butoxycarbonyl-4-aminophenylalaninol, represented by formula (V)
d) a ring closure of the compound of formula (V) to give (S)-4-(4-aminobenzyl)-2-oxazolidinone, represented by formula (VI)
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)
f) Fischer reaction of the compound of formula (VII) to give the compound of formula (I)
Preferably, the process is used to prepare a compound of formula (I) wherein A is cyclobutyl. Most preferably the process is used for the preparation of 4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)oxazolidin-2-one.
Suitably, one or more of steps a) to f) are carried out using a cone 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 preference to sodium hydrogen carbonate and is preferably added prior to the n-butyl chloroformate. The reaction is conveniently carried out at a non-extreme temperature, suitably in the range 5-60° C. Preferably the reaction is carried out at 15-35° C. In a particularly preferred embodiment the addition of sodium carbonate takes place at a temperature of approximately 20° C. and the addition of N-butyl chloroformate takes place at a temperature of approximately 30° C.
The reduction step b) is conveniently carried out in the presence of an organic solvent, e.g. ethyl acetate or ethanol. Preferably step b) is carried out by a one pot procedure using the ethyl acetate solution of the compound of formula (III) which results from step a). Suitably, step b) is carried out by hydrogenation, preferably in the presence of a catalyst such as palladium charcoal. The reaction may be carried out under an atmosphere of nitrogen using hydrogen at normal atmospheric pressure at room temperature. Hydrogenation is preferably carried out at approximately 20 psi of hydrogen at an elevated temperature e.g. 30° C. to 50° C. The resulting ethyl acetate solution of the compound of formula (IV) is preferably converted into a butanol solution which can be used directly, as part of a one pot procedure, in step c). This conversion can conveniently be carried out by partial distillation of the ethyl acetate solution followed by addition of butanol and fractionation to remove the ethyl acetate.
The methyl ester reduction of step c) is conveniently carried out in the presence of a solvent e.g. SVM or n-butanol. Preferably step c) is carried out as part of a one pot procedure by preparing a n-butanol solution from the ethyl-acetate solution of the compound of formula (IV) and then directly reducing the n-butanol solution. The reduction is preferably effected using sodium borohydride and is conveniently carried out at a non-extreme temperature suitably 20-40° C. Preferably, the reduction is carried out in two phases; the first phase being carried out under nitrogen at a temperature of approximately 25° C.; and the second phase being carried out at approximately 30° C. The resulting n-butanol solution of the compound of formula (V) can then be dried using hydrochloric acid and ammonia. The dry n-butanol solution can be used directly in step d) as part of a one pot procedure.
Step d) is preferably carried out on a dry solution, e.g. a dry butanol solution, of the compound of formula (V). Such a dry butanol solution is advantageously prepared by drying the n-butanol solution which is produced by step c). The dry n-butanol solution is preferably decolourised using charcoal before carrying out the ring closure reaction. The ring closure can be conveniently effected using sodium methoxide, suitably in an alcoholic solvent e.g. methanol. Most preferably, the ring closure is carried out using a 30% solution of sodium methoxide in methanol. The reaction is preferably carried out at an elevated temperature which is suitably in the range 50-120° C. Preferably the reaction is carried out at approximately 85° C. The resulting compound of formula (VI) may then be isolated. This isolation can be carried out by standard ce

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