New synthesis of Mephenoxalone

Mephenoxalone ( 1 ) was synthesized through a silanizated intermediate prepared from the addition of trimethylsilyl cyanide (TMSCN) to ( o -methoxy)phenoxyacetaldehyde ( 10 ). Three different methods were established to synthesize this aldehyde. Alkylation of guaiacol with bromoacetaldehyde diethyl acetal, followed by acid hydrolysis of acetal group gave the highest overall yield (49%) for the aldehyde 10. Different reagents as ZnI 2 , Montmorillonite K10, (+)- Eu(tfc) 3 and (+)-Yb(tfc) 3 were used in the addition of TMSCN to the aldehyde giving very good yields with all catalysts.


Introduction
Oxazolidinone compounds are important because their broad spectra of pharmacological properties.Especially, 5-aryloxymethyl-2-oxazolidines are a group of compounds which shown activity as interneuron blocking agents or depressants of central synaptic transmission.They are generally antagonists of strychnine convulsions and have been used as skeletal muscle relaxants, anticonvulsants, and tranquilizers.3][4][5][6] In the other hand, another group of oxazolidinones typified by Eperozolid (3) and Lynezolid (4) (marketed as Zyvox TM ), represent a new class of synthetic antibacterial agents with potent activity against clinically important susceptible and resistant Gram-positive pathogens.This class of compounds has a novel mechanism of action that shows selective and unique binding to 50S ribosomal subunit, inhibiting bacterial translation at initiation phase of protein synthesis. 7It is suggested that oxazolidinones act by disrupting the processing of N-formylmethionyl t-RNA by the ribosome. 8 The synthesis of Mephenoxalone was reported by Lunsford in 1960. 9This method consisted in the fusion of one equivalent of urea with one equivalent of 3-o-methoxyphenoxy-1,2propanediol at 180-200 o C to produce the crude oxazolidinone which was further purified by fractional distillation and crystallization to gave a 67% isolated product yield.1][12][13] Previously, we reported the synthesis of a bronchodilator blocker Fenspiride (5) 14 and continuing our interest in cyclization reactions using bistrichloromethyl carbonate (BTC or triphosgene) and the addition of trimethylsilyl cyanide to aldehydes, 15 we proposed a new methodology for the synthesis of Mephenoxalone through silanized intermediate.

Results and Discussion
Our goals in this work were to synthesize Mephenoxalone by the addition of trimethylsilyl cyanide to (o-methoxy)phenoxyacetaldehyde (10) and compare the efficiency of different catalysts in the addition step.The aldehyde used as starting material is not commercially available and was necessary to be prepared.Three different methods were proposed for the synthesis of aldehyde 10 (Scheme 1). 1) Direct alkylation of guaiacol with chloroacetaldehyde under basic conditions with 26% yield.2) Alkylation of guaiacol with ethyl bromoacetate using K 2 CO 3 in acetone followed by reduction of the corresponding ethyl (o-methoxy)phenoxyacetate (7) to obtain (o-methoxy)phenoxyethanol (8).This alcohol was oxidized with PCC leading to the aldehyde 10.The overall yield with this method was 16%.3) Alkylation of guaiacol with bromoacetaldehyde diethyl acetal, 25% NaOH aqueous solution and HMPA as solvent gave the (o-methoxy)phenoxyacetaldehyde diethyl acetal (9) which was hydrolyzed with HCl in 1,4dioxane to gave the aldehyde 10. 16 The overall yield with this method was 49%.Comparing these results, we concluded that the best synthetic route was method 3 because required only two reaction steps and gave the highest overall yield.HCl Scheme 1. Synthesis of (o-methoxy)phenoxyacetaldehyde (10).
The addition of TMSCN to the aldehyde 10 was carried out with ZnI 2 , Montmorillonite K10, (+)-Eu(tfc) 3 and (+)-Yb(tfc) 3 in order to obtain the silanized intermediate 11 with good yield in each case (88-96%) (Scheme 2 and Table 1).4][25] Here, europium and ytterbium camphorates were used to establish their catalytic capacity and asymmetric induction in the addition of TMSCN to the carbonyl group.They generated excellent activation in both cases, 96% and 88% yield respectively, but asymmetric induction was not observed.
ARKAT USA, Inc.The silyl ether 11 was reduced using LiAlH 4 giving the β-aminoalcohol 12 with 63 % yield. 26he final step consisted in the cyclization of 12 with BTC to give the oxazolidinone 1 in 70% yield (Scheme 2).The overall yield from aldehyde 10 to Mephenoxalone (1) was 42%. 1 H and 13 C NMR of this product were obtained and signals are in accordance with the date reported in literature. 27

Conclusions
In summary, the process of addition of trimethylsilyl cyanide to aldehyde 10 allowed us to develop a new methodology to synthesize Mephenoxalone.This reaction occurs with very good yields using different catalysts and subsequent reduction and cyclization with BTC led to form Experimental Section General Procedures.Melting points were obtained on an Electrothermal 88629 apparatus and are uncorrected.Infrared spectra (IR) were recorded on a Perkin Elmer FT-IR 1600 spectrophotometer.Nuclear magnetic resonance 1 H and 13 C spectra at 50.289 Hz were recorded on a Varian Mercury 200 MHz Spectrometer in CDCl 3 and DMSO-d 6 with TMS as internal standard.Mass spectra were obtained on a Hewlett-Packard 5989 by EI at 70 eV by direct insertion.Elemental analysis for carbon and hydrogen were performed by Galbraith Laboratories, Incorporated (Knoxville, TN).

Table 1 .
Addition of TMSCN to aldehyde 10