Field of the invention

The present invention provides an improved process for the preparation of Linezolid of formula (I) and (R)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methanol of formula (II) which is a key intermediate for the preparation of Linezolid of formula (I).

Background of the invention

Linezolid is chemically known as N-[[(5S)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide and marketed by Pfizer in US under brand name Zyvox. Linezolid is a synthetic antibacterial agent of the oxazolidinone class. It is used for the treatment of infections caused by multi-resistant bacteria including streptococci and methicillin-resistant Staphylococcus aureus.

Linezolid was first disclosed in U.S. Pat. No. 5,688,792. The process for synthesis is as disclosed in Scheme-I

In the process disclosed above the key intermediate (II) is obtained by reacting N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline of formula (IVa) with (R)-glycidyl butyrate of formula (III) in the presence of n-butyl lithium to obtain compound of formula (II).

Disadvantage of the process disclosed in U.S. Pat. No. 5,688,792 is that it involves use of n-butyl lithium. Due to its explosive nature it is difficult to handle at plant scale. Also, the said reaction is carried out at temperature of -78°C, which is difficult to attain during commercial production. Further the intermediate obtained requires purification by column chromatography. Column chromatography is a cumbersome technique and difficult to practice during commercial scale production.

The process for the preparation of Linezolid is also disclosed in Journal of Medicinal Chemistry (1996), 39(3), 673-9, U.S. Pat. Nos. 6,492,555, 5,837,870, 6,887,995, 7,307,163, 7,429,661, etc.

None of the above mentioned prior arts offer safe and cost effective method for the production of compound of formula (II).

Object of the invention

It is an object of the present invention to provide a process for the preparation of Linezolid formula (I).

Another object of the present invention is to provide process for the preparation of compound of formula (II).

Summary of the invention

An aspect of the present invention provides a process for the preparation of Linezolid of formula (I) comprising a step of

reacting compound of formula (IV), wherein R is Hydrogen or Nitrogen protecting group, with compound of formula (III) in presence of n-butyl lithium and n-butanol in a suitable solvent to obtain compound of formula (II)

Another aspect of the present invention provides an improved process for the preparation of compound of formula (II) comprising of

reacting compound of formula (IV), wherein R is Hydrogen or Nitrogen protecting group, with compound of formula (III) in presence of n-butyl lithium and n-butanol in a suitable solvent to obtain compound of formula (II)

Yet another aspect of present invention provides a process for preparation of Linezolid and its key intermediate which is simple, safe, cost-effective and easy to follow at commercial scale.

Detailed description of the invention

The present invention provides a process for the preparation of Linezolid of formula (I) comprising a step of

reacting compound of formula (IV), wherein R is Hydrogen or Nitrogen protecting group, with compound of formula (III) in presence of n-butyl lithium and n-butanol in a suitable solvent to obtain compound of formula (II)

Another preferred embodiment of the present invention provides an improved process for the preparation of compound of formula (II) comprising of

reacting compound of formula (IV), wherein R is Hydrogen or Nitrogen protecting group, with compound of formula (III) in presence of n-butyl lithium and n-butanol in a suitable solvent to obtain compound of formula (II)

The compound of formula (IV) can be prepared by any process disclosed in the prior art or methods known perse.

In one of the preferred embodiment compound of formula (IV) wherein R is Nitrogen protecting group prefereably carbobenzoxy group is prepared by following the process disclosed in Scheme-II.

The compound of formula (IV) is converted to compound of formula (II) by reacting compound of formula (IV), with compound of formula (III) i.e. (R)-(-)-Glycidyl butyrate in the presence of n-butyl lithium and n-butanol in a suitable solvent.

The example of suitable solvent includes but is not limited to tetrahydrofuran. The reaction is carried out in the temperature range of -30°C to 30°C. The reaction proceeds via formation of lithium salt of n-butanol.

After the completion of reaction the reaction mass is work-uped and the product obtained is used as such without further purification for the next step.

Compound of formula (II) is converted to Linezolid via formation of mesylate which is converted to azide and reduced and acylated to obtain Linezolid.

The compound of formula (II) can be converted to Linezolid by any method known in the art or by method know perse.

The advantages of process of present invention are:
1. It does not require temperature as low as -78°C, which is practically difficult to maintain during scale up process.
2. The product obtained does not require further purification by cumbersome process such as column chromatography which is difficult to perform at commercial scale.

The following examples illustrate the invention further. It should be understood however, that the invention is not confined to the specific limitations set forth in the individual example but rather to the scope of the appended claims.

Examples

Example 1: Preparation of 3-Fluoro-4-morpholinyl nitrobenzene.

To a solution of Methanol (90ml) and 3, 4-Difluoronitrobenzene (100g) at 25-30oC add Morpholine (115g) drop wise at 25-30oC in more than 1 hour under stirring. Stir the reaction mass at 25-30oC for 1-2 hours. Then add slowly Water (400ml) with stirring the reaction mass at 25-30oC for 1 hour. Filter the solid & wash it with water. The solid is dried at 55-60oC. Yield: 1.408.; Percentage 99.0 %w/w.

Example 2: Preparation of N-Carbobenzoxy-3-fluoro-4-morpholinylaniline

Take 3-Fluoro-4-morpholinyl nitrobenzene (100g), Methanol (1000ml) and 10% palladium on carbon catalyst (2.0g 50% wet) in the autoclave at 20-30oC for 3-4 hrs at 1-2kg hydrogen pressure. Filter it and wash the hyflo bed by methanol (50ml×2). Apply vacuum to remove traces of methanol & add Acetone (100ml) to distill out completely below 70oC. Cool it & further add Acetone (400ml) and sodium carbonate (46.9g) to the residue. After cooling the mix at 0-5oC, 166g of Benzyl chloroformate (50% solution in Toluene) was added slowly at 0-5oC under stirring. Water (800ml) & n-Hexane (100ml) are added at 0-5oC for 1 hour at constant stirring. The mixture was filtered & solid was washed with water (200ml×2) and n-Hexane (100ml). The solid is dried at 55-60oC. Yield: 1.43.; Percentage 97.9 %w/w.

Example 3: Preparation of (R)-[N-3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methanol.

Take n-Butanol (51.5g) and THF (100ml) at 20-30oC under Nitrogen atmosphere. After cooling the mix add slowly n- Butyl lithium (1.6M in hexane) (391.7g) at 10 to 20oC & maintain it for 45-60 minutes. Take THF (500ml) and N-Carbobenzoxy-3-fluoro-4-morpholinylaniline (100g) at 20-30oC under Nitrogen atmosphere. Cool the mix at -15 to -5oC under stirring. To this solution add slowly n- Butyl lithium solution & maintain for 45-60 minutes at -15 to -5oC, to this solution add slowly (R)-(-) Glycidyl butyrate (48.0g) & maintain for 1 hour at -10 to -5oC. After completing addition raise the temperature to 8-13oC and maintain for 1 hour & then take it to 13-15oC and maintain for 4-5 hours. Organic layer was separated by water (800ml) and Ethyl acetate (300ml). Filter & wash the solid with mix of Ethyl acetate- n-Hexane & dried in air tray dryer at 55-60oC. Yield: 0.765.: Percentage 85%w/w.

Example 4: Preparation of (R)-[N-3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl methane sulfonate

Triethyl amine (68.2g), Methane sulfonyl chloride (48.3g) are added to a flask containing Dichloromethane (1900ml) and (R)-[N-3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methanol (100g) at 20-30oC with constant stirring for 2-3 hours. After cooling & filtration wash the solid with Dichloromethane followed by water wash & dried in air tray dryer. Yield: 1.20.: Percentage 95%w/w.

Example 5: Synthesis of (R)-[N-3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl azide.

Reflux the mix of Dimethyl formamide (250ml), (R)-[N-3-(3-Fluoro-4-morpholinyl phenyl)-2-oxo-5-oxazolidinyl] methyl methane sulfonate (100g) and Sodium azide (24.3g) at 60-65oC & maintain it for 6-7 hours. Cool the mix & add water (450ml) with constant stirring for one hour at 20-30oC. Filter it; wash the solid with mix of Dimethyl formamide - water (1:1) and with water & dried at 55-60oC. Yield: 0.82.: Percentage 95%w/w.

Example 6: Synthesis of Linezolid Crude.

Ethyl acetate (3500ml) and 10% palladium on carbon catalyst (6.0g) are added in autoclave having (R)-[N-3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl azide (100g) at 20-30oC. Cool the reaction mass & maintain 2-3kg hydrogen pressure at 15-20oC for 6-7 hrs. Filter it & wash the hyflo bed by Ethyl acetate (100ml×2). Then add the Triethyl amine (35.1g) & Acetic anhydride (29.9g) slowly at 25-30oC under stirring. Cool the mix, filter it and wash the solid with chilled (0-5oC) Ethyl acetate (100 ml) followed by water (100ml×2). Finally product is dried at 55-60oC. Yield: 0.85.: Percentage 81%w/w.

Example 7: Synthesis of Linezolid Pure.

Reflux the Acetone (1020ml) and Linezolid crude (100g) at 55-60oC for the 30 minutes. Filter the hot turbid solution & wash it with hot (55-60oC) acetone (50ml). Cool the reaction mixture at -5 to 0oC for 1 hour, wash the solid with chilled (-5 to 0oC) acetone (50ml). After drying the Linezolid semi pure (77g) add n-Propanol (308ml) reflux it at 95-100oC for 30 min & filter it by hot solution through hyflo bed. Cool the mix to 0-5oC for 1 hour and wash the solid with chilled (0-5oC) n-Propanol (77ml). Dry the material at 55-60oC. Yield: 0.73.: Percentage 73%w/w.