Process for the preparation of metaxalone

Details Process for the preparation of metaxalone Process for the preparation of metaxalone

2002-04-18

2003-03-25

Chang, Ceila (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S225000, C564S336000, C564S348000, C568S655000, C549S555000, C549S563000, C560S179000

Reexamination Certificate

active

06538142

ABSTRACT:

The present invention relates to a process for the preparation of metaxalone or 5-(3,5-dimethylphenoxymethyl)-2-oxazolidinone.
The latter is a known muscle relaxing agent of the group of 5-aryloxymethyl-oxazolidones, and was initially described in U.S. Pat. No. 3,062,827. In this patent, different routes of synthesis of metaxalone are proposed. For example, the compound is prepared by reacting 3-(3′,5′-dimethylphenoxy)-1,2-propanediol and urea at a temperature of 195-200° C. Alternatively, the selected 3-phenoxy-1-chloro-2-propanol may be reacted with urea instead of the phenoxy-1,2-propanediol under the same conditions. The 5-(3′,5′-dialkylphenoxymethyl)-2-oxazolidones may also be prepared by reacting a selected 3-phenoxy-2-hydroxy-1-propylcarbamate and urea in equimolar quantities and at elevated temperatures.
The synthesis reported in GB1104773 comprises the reaction of 3,5-dimethyl-phenol with triglycidyl isocyanurate in an organic solvent using a phenol/isocyanurate molar ratio of about 1:3.
Object of this invention is a process for the preparation of metaxalone, which comprises:
a) reaction of 3,5-dimethylphenol with epichlorohydrin to obtain a mixture of 1-(3,5-dimethylphenoxy)2,3-epoxy propane (1) and 1-(3,5-dimethylphenoxy)-3-chloro-2-propanol (2):
b) reaction of the mixture of (1) and (2) obtained from step (a) with benzylamine to give (3):
c) reduction of (3) with hydrogen in presence of ammonia, to give (4):
d) reaction of (4) with dimethylcarbonate in the presence of a strong base to give 5-(3,5-dimethylphenoxymethyl)-2-oxazolidinone (5):
In step (a) the mixture of reactants is usually heated at reflux temperature in the presence of a quaternary ammonium salt for a period sufficient to have complete conversion into (1) and (2). Once the reaction is completed, the excess epichlorohydrin as well as any 1,3-dichloropropanol by-product are distilled off.
In step (b) a mixture of (1) and (2) is added to an excess of benzylamine, heating to a temperature of 130°-135° C. At the end a strong base is added to free benzylamine which is distilled off.
The reduction step (c) can be carried out with gaseous hydrogen in the presence of a Pd/C catalyst and ammonia. Once the reaction (which is monitored by HPLC) is terminated, the catalyst is filtered off, the pH is adjusted at 10-13 units and the solution is extracted with organic solvents. The organic layers are collected and extracted with an acidic aqueous solution at pH 4, the organic phase is discarded. Solvent is added to the aqueous phase and the mixture is made alkaline by addition of sodium hydroxide. The aqueous layer is separated and product (4) is recovered by distilling off the solvent.
In step (d) product (4) is reacted with dimethylcarbonate in the presence of a metal alkoxide, preferably sodium methoxide, at reflux temperature. The excess dimethylcarbonate is distilled off and product (5) is taken up with an organic solvent and washed with aqueous hydrogen chloride and sodium hydroxide. The organic solution is dried and the product crystallizes by cooling.
The following example illustrates the invention in greater details.


REFERENCES:
patent: 1487641 (1967-07-01), None
Takahashi et al, J. Am. Chem. Soc. 1990, 112, 5876-5878.*
Vigroux et al, J. Med. Chem. 1995, 38, 3983-3994.

Affiliated with

Also associated with

Rating

Process for the preparation of metaxalone does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the preparation of metaxalone, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of metaxalone will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3048571