Method for producing 5-aryloxymethyl-2-oxazolidinones

Details Method for producing 5-aryloxymethyl-2-oxazolidinones Method for producing 5-aryloxymethyl-2-oxazolidinones

2002-08-19

2003-05-13

McKane, Joseph K. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06562980

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a method for making 5-aryloxymethyl-2-oxazolidinones having the general formula (I) of:
wherein R
1
and R
2
are hydrogen, halogen, alkyl, or alkoxyl group and wherein the alkyl or alkoxyl group contains no more than three carbon atoms in straight or branched chain. In particular, the invention relates to a method for synthesizing 5-aryloxymethyl-2-oxazolidinones by reacting a triglycidyl isocyanurate (TGIC) with an unsubstituted or a mono- or di-substituted phenol.
BACKGROUND OF THE INVENTION
5-Aryloxymethyl-2-oxazolidinones are a group of compounds which is well-known in having activity as interneuronal blocking agents or depressants of central synaptic transmission. The compounds have the general formula of:
where R
1
and R
2
can be hydrogen, halogen, alkyl, or alkoxyl group.
These compounds, characterized by the presence of specific substituents in specific positions on the phenyl ring, have been found to have superior activity on blocking the abnormal nervous impulses which give rise to spasm. They are generally antagonists of strychnine convulsions and have been for use as skeletal muscle relaxants, anticonvulsants, and tranquilizers.
Two particular compounds of this group, metaxalone and mephenoxalone, are especially useful for their skeletal muscle relaxant and/or anxiolytic effects. Metaxalone, having the chemical name of 5′-(3,5-dimethylphenoxymethyl)-2-oxazolidinone, is a skeletal muscle relaxant. It acts in the central nervous system (CNS) to produce the muscle relaxant effects. The chemical structure of metaxalone is shown as formula (II):
Metaxolone is currently commercially available in the U.S. under the tradename of Skelaxin® (as a 400 mg, pale rose, scored tablet) and distributed by Elan Pharmaceuticals (Cedar Knolls, N.J.). According to the statements in Skelaxin® package insert, the mechanism of action of metaxalone in humans has not been established, but may be due to general central nervous system depression. It has no direct action on the contractile mechanism of striated muscle, the motor end plate or the nerve fiber. Skelaxin® is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions.
Mephenoxalone, having the chemical name of 5-(2-methoxyphenoxy)methyl)-2-oxazolidinone, is a skeletal muscle relaxant, is a skeletal muscle relaxant as well as an anxiolytic. The chemical structure of mephenoxalone is shown as formula (III):
The method for making mephenoxalone (5-o-methoxyphenoxymethyl-2-oxazolidone) is disclosed in U.S. Pat. No. 2,895,960, issued to Lunsford et al. The method involves a fusion of about 1 mol equivalents of urea with about 1 mol equivalent of 3-o-methoxyphenoxy-2-hydroxy-1-propyl carbamate (FIG.
1
). The reactants are commercially available. The method described in U.S. Pat. No. 2,895,960 produces a crude oxazolidone, which may be further purified by fractional distillation or recrystallization.
Metaxalone can be produced by the method described in U.S. Pat. No. 3,062,827, issued to Lunsford et al. The patent discloses generally the process of making 5-(3,5-dialkylphenoxymethyl)-2-oxazolidones which involves a fusion of a selected 3-phenoxyl-1,2-propanediol (having the predetermined substituents on the phenyl ring) with urea at a 1:2 molar ratio, with or without a solvent (FIG.
2
). Alternatively, a selected 3-phenoxy-1-chloro-2-propanol may be reacted with urea instead of the phenoxy-1,2-propanediol, using the same molar ratios and under the same reaction conditions. Furthermore, the 5-(3,5-dialkylphenoxymethyl)-2-oxazolidones may be prepared by reacting a selected 3-phenoxy-2-hydroxy-1-propyl-carbamate and urea. The method described in U.S. Pat. No. 3,062,827, similar to that of U.S. Pat. No. 2,895,960, produces a crude oxazolidone, which requires further purification by fractional distillation or recrystallization.
Lunsford et al.,
J. Am. Chem. Soc.
(1960), 82:1166-1171, further explores the sequence of reaction for making 5-aryloxymethyl-2-oxazolidinones as described in U.S. Pat. Nos. 2,895,960 and 3,062,827. Its finding confirms that in order to locate unequivocally the aryloxymethyl group of the compounds at position 5 (rather than position 4) of the oxazolidinone ring, the reaction should be subject to basic hydrolysis which gives rise to a 1-amino-3-(o-methoxyphenoxy)-2-propanol, which is then fused with urea to produce 5-aryloxymethyl-2-oxazolidinones.
In the invention to be presented in the following sections, a novel method for synthesizing a 5-aryloxymethyl-2-oxazolidinone by fusing about 1 molar equivalent of a triglycidyl isocyanurate (TGIC) with 3 molar equivalents of a substituted phenol is introduced. The present method differs from the prior art methods particularly for its use of different starting materials and different molar ratios of the reactants.
SUMMARY OF THE INVENTION
The present invention provides a process for preparing 5-aryloxymethyl-2-oxazolidinones having the general formula (I) of:
in which R
1
and R
2
are hydrogen, halogen, alkyl, or alkoxyl group and in which the alkyl or alkoxyl group contains no more than 3 carbon atom in straight or branched chain.
The process includes a reaction between a triglycidyl isocyanurate (TGIC) of formula (IV):
and an unsubstituted or a mono- or di-substituted phenol of formula (V):
wherein R
1
and R
2
are the same as those shown in formula (I). Preferably, the reaction is performed in the presence of a base. The preferred examples of base include, but are not limited to, NaOH and NH
4
OH, and most favorably, NaOH. The preferred molar ratio of TGIC and the unsubstituted or substituted phenol is about 1:3.
5-Aryloxymethyl-2-oxazolidinones are compounds that can be used as anticonvulsants, muscle relaxants, tranquilizers, and/or anxiolytics in humans. Examples of 5-aryloxymethyl-2-oxazolidinones include metaxolone, which is 5-(3,5-dimethylphenoxymethyl)-2-oxazolidinone; and mephenoxalone, which is 5-(2-methoxyphenoxy)methyl)-2-oxazolidinone. Both metaxolone and mephenoxalone are skeletal muscle relaxants. Mephenoxalone is also an anxiolytic.
TGIC and the unsubstituted or mono- or di-substituted phenol are perferred to be dissolved in a solvent and reacted under reflux condition. Examples of the solvent that can be used in the process include, but is not limited to, acetone, ethanol, chloroform, and ethyl acetate. The preferred solvent is acetone, which can be used in combination with water.
The process is also preferably performed under anaerobic condition such as carrying out under nitrogen gas. The time required for complete reaction is about 10 to 60 hours, preferably 12 to 24 hours.
After the completion of the reaction, the crude 5-aryloxymethyl-2-oxazolidinone is further purified by partitioning the crude 5-aryloxymethyl-2-oxazolidinone between a water layer and an ethyl acetate layer. The purified 5-aryloxymethyl-2-oxazolidinone is recovered from the ethyl acetate layer. The preferred volume ratio between the ethyl acetate layer and the water layer is about 50:30. Preferably, the partitioning step is repeated three times. The purified 5-aryloxymethyl-2-oxazolidinone is collected from the ethyl acetate layer by letting the ethyl acetate layer sit for a suitable period of time to allow precipitation of the purified 5-aryloxymethyl-2-oxazolidinone. The precipitant is then collected by filtration and dried, using conventional methods. The purified 5-aryloxymethyl-2-oxazolidinone is in white, powdery form.
The present invention also provides a method for relieving patients with musculoskeletal discomforts by administering the 5-aryloxymethyl-2-oxazolidinone prepared by the method as described above to the patients. Examples of the 5-aryloxymethyl-2-oxazolidinone includes, but is not limited to, metaxalone or mephenoxalone. The 5-aryloxymethyl-2-oxazolidinone is preferred to be orally administered to patients, such as in the form of tablets or capsules.


REFERENCES:
patent: 2895960 (1959-07-01

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