WO2008006096A1

WO2008006096A1 - Metaxalone synthesis

Info

Publication number: WO2008006096A1
Application number: PCT/US2007/073015
Authority: WO
Inventors: Iulia Demian; Alice Digiulian Mcclure
Original assignee: Boehringer Ingelheim Chemicals Inc
Current assignee: Boehringer Ingelheim Pharmaceuticals Inc
Priority date: 2006-07-07
Filing date: 2007-07-09
Publication date: 2008-01-10
Anticipated expiration: 2009-01-07

Abstract

A process for preparing metaxalone comprising reacting 3-(3,5-dimethylphenoxy)-1-amino-2-propanol with methyl carbamate in the presence of a strong base to obtain metaxalone.

Description

METAXALONE SYNTHESIS

Field of the Invention

The present invention relates to an efficient synthesis of metaxalone.

Background of the Invention

Metaxalone or 5-[(3,5-dimethylphenoxy)methyl]-2-oxazolidinone is a skeletal muscle relaxant having the following chemical structure:

Preparation of metaxalone is described in Lunsford et ah, J. Am. Chem. Soc. 82, 1166 (1960) and U.S. Patent No. 3,062,827. Metaxalone is a central nervous system depressant that has sedative and skeletal muscle relaxant effects and is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions.

There is continuing interest in metaxalone as a pharmaceutical, for example, U.S. Patent No. 6,683,102, entitled Methods of Using Metaxalone in the Treatment of Musculoskeletal Conditions and U.S. Patent No. 6,407,128, entitled Method for Increasing the Bioavailability of Metaxalone describe methods of administering metaxalone in combination with food; U.S. Patent No. 6,572,880, entitled Methods and Transdermal Compositions for Pain Relief describes compositions of an amine containing compound having biphasic solubility and an agent such as metaxalone which enhances the activity of the amine containing compound; U.S. Patent No. 6,538,142, entitled Process for the Preparation of Metaxalone describes a reaction/reduction process for obtaining metaxalone; U.S. Patent No. 4,722,938, entitled Methods for Using Musculoskeletal Relaxants describes methods of using musculoskeletal relaxants such as metaxalone; and U.S. Patent Application Publication No. 2005/0063913 entitled Novel Metaxalone Compositions describes nanoparticulate compositions comprising metaxalone.

Summary of the Invention

The invention is directed to a more efficient and economic synthesis route for metaxalone consisting of a single reaction step. The process involves reacting 3-(3,5- dimethylphenoxy)-l-amino-2-propanol with methyl carbamate in the presence of a strong base such as LiNH₂, sodium methylate, KOH, or NaOH to obtain metaxalone. The crude metaxalone is then isolated and purified by crystallization from butyl acetate. The overall yield for this process is approximately 65%-68% pure metaxalone. The process is illustrated in Scheme 1 below.

Scheme 1

Detailed Description of the Invention In a specific embodiment, the term "about" or "approximately" means within 20%, preferably within 10%, and more preferably within 5% of a given value or range. The yield of each of the reactions described herein is expressed as a percentage of the theoretical yield. Experimental Examples

Optimum reaction conditions and reaction times may vary depending on the particular reagents used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in this Experimental Examples section. Typically, reaction progress may be monitored by high performance liquid chromatography (HPLC) or thin layer chromatography (TLC), if desired, and intermediates and products may be purified by chromatography on silica gel and/or by recrystallization.

Example 1 :

50 g (0.2564 mol) of 3-(3,5-dimethylphenoxy)-l-amino-2-propanol was reacted at 145°C- 150⁰C for 10 hours with 25.0 g (0.333 mol) of methyl carbamate in the presence of 0.005- 0.006 mol of base (LiNH₂, methanolic solution of NaOCH₃, NaOH, or KOH). The completion of the reaction is checked by HPLC. The hot reaction mixture was treated with 100 mL of water and 150 mL of butyl acetate. The pH of the mixture was adjusted to 5 with acetic acid. Two layers were separated at 80°C-90°C. The residual water in the organic layer is separated by distillation. Upon cooling, the organic phase separated metaxalone crude at 70%-72% yield. The crude metaxalone is purified by crystallization from a carbon treated butyl acetate solution. Yield: 92%-95%

Further experiments concerning the reaction parameters have shown that: a. the reaction time is solely a function of temperature; b. the amount of 3-(3,5-dimethylphenoxy)-l-amino-2-propanol residual (unreacted) starting material is also a function of temperature; c. the concentration of the impurities is a function of both temperature and methyl carbamate stoichiometry, where lower temperatures and lower mole ratios of methyl carbamate to 3-(3,5-dimethylphenoxy)-l-amino-2-propanol minimize the impurities formation; and d. the yield is increased at lower mole ratios of methyl carbamate to 3 -(3, 5- dimethylphenoxy)-l-amino-2-propanol and at higher temperatures. In summary, the reaction should be run at the lower temperature in order to minimize the formation of impurities and lower molar ratio of methyl carbamate to 3 -(3, 5- dimethylphenoxy)-l-amino-2-propanol is preferable.

Example 2:

The methyl carbamate stoichiometry is determinant for the formation of the major impurity. The limit of diminishing returns has been demonstrated to be at 1.25-1.35 equivalents of methyl carbamate. As shown in Table 1, the data also show that LiNH₂ or CH₃ONa can be used interchangeably.

The 3-(3,5-dimethylphenoxy)-l-amino-2-propanol starting material has to be of good quality including chemical purity and color. Colored impurities are only partially removed by the butyl acetate treatment and impact the quality of the final product with respect to color. Accordingly, it is advantageous for carbon treatment to be applied either to the crude or to the final purification step.

In addition, the filtrate from the final purification can be recycled in part. Unreacted 3-(3,5- dimethylphenoxy)-l-amino-2-propanol can be separated from the concentrated filtrates and can be recycled after separation by filtration and drying. A better alternative would be to run the reaction as close to completion as practical.

Claims

What is claimed is:

1. A process for preparing metaxalone comprising reacting 3-(3,5-dimethylphenoxy)- l-amino-2-propanol with methyl carbamate in the presence of a strong base to obtain metaxalone.

2. The process according to claim 1, wherein the strong base is LiNH₂, sodium methylate, KOH, or NaOH.

3. The process according to claim 2, wherein the strong base is LiNH₂.

4. The process according to claim 2, wherein the strong base is sodium methylate.

5. The process according to claim 2, wherein the strong base is KOH.

6. The process according to claim 2, wherein the strong base is NaOH.

7. The process according to claim 1, wherein the ratio of 3-(3,5-dimethylphenoxy)-l- amino-2-propanol to methyl carbamate molar ratio is about 1.2 to about 2.0.

8. The process according to claim 2, wherein the ratio of 3-(3,5-dimethylphenoxy)-l- amino-2-propanol to methyl carbamate molar ratio is about 1.2 to about 2.0.

9. The process according to claim 1, further comprising purifying and isolating the metaxalone by crystallization from butyl acetate.

10. The process according to claim 2, further comprising purifying and isolating the metaxalone by crystallization from butyl acetate.