FIELD OF THE INVENTION

The invention relates to an improved process for the preparation of oxazolidinone compounds.

BACKGROUND OF THE INVENTION

Oxazolidinones represent a class of synthetic antimicrobial agents. Oxazolidinones exhibit activity against Gram-positive human and veterinary pathogens including methicillin-resistant Staphylococcus aureus (MRSA)  vancomycin resistant enterococci (VRE) and b-lactam resistant Streptococcus pneumoniae (PRSP). PCT Application No PCT/IB2007/002758 discloses several substituted piperdinophenyl oxazolidinones including a compound of Formula (I):

The present invention provides a process for preparing a compound of Formula (I).

SUMMARY OF THE INVENTION

Accordingly  there is provided a process for preparation of a compound of Formula (I).

In one general aspect  there is provided a process for preparation of a compound of Formula (I):

comprising 
(a) reacting a compound of Formula (IV) with trimethylsulfoxonium iodide or trimethylsulfonium iodide in presence of a base and a solvent to obtain a compound of Formula (V):

(b) reacting a compound of Formula (V) with methanol in presence of a base to obtain a compound of Formula (VI)

(c) reducing the compound of Formula (VI) to obtain a compound of Formula (VII)

(d) reacting a compound of Formula (VII) with benzylchloroformate in presence of a solvent to obtain a compound of Formula (VIII)

(e) reacting a compound of Formula (VIII) with N-[(2S)-2-(acetyloxy)-3-chloropropyl]-acetamide to obtain the compound of Formula (I).

In another general aspect  there is provided a process for preparation of a compound of Formula (IV) by reacting a compound of Formula (II) with a compound of Formula (III) in presence of a base and a solvent.

The details of one or more embodiments of the inventions are set forth in the description below. Other features  objects and advantages of the inventions will be apparent from the following description including claims.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made to the exemplary embodiments  and specific language will be used herein to describe the same. It should nevertheless be understood that no limitation of the scope of the invention is thereby intended. Alterations and further modifications of the inventive features illustrated herein  and additional applications of the principles of the inventions as illustrated herein  which would occur to one skilled in the relevant art and having possession of this disclosure  are to be considered within the scope of the invention. It must be noted that  as used in this specification and the appended claims  the singular forms "a " "an " and "the" include plural referents unless the content clearly dictates otherwise.

In some embodiments  there is provided a process for preparation of a compound of Formula (I):

comprising 

(a) reacting a compound of Formula (IV) with trimethylsulfoxonium iodide or trimethylsulfonium iodide in presence of a base and a solvent to obtain a compound of Formula (V):

(b) reacting a compound of Formula (V) with methanol in presence of a base to obtain a compound of Formula (VI)

(c) reducing the compound of Formula (VI) to obtain a compound of Formula (VII)

(d) reacting a compound of Formula (VII) with benzylchloroformate in presence of a solvent to obtain a compound of Formula (VIII)

(e) reacting a compound of Formula (VIII) with N-[(2S)-2-(acetyloxy)-3-chloropropyl]-acetamide to obtain the compound of Formula (I).

Compound of Formula (V)

In general  a compound of Formula (V) is prepared by reacting a compound of Formula (IV) with trimethylsulfoxonium iodide or trimethylsulfonium iodide in presence of a base and a solvent.

A wide variety of bases and solvents can be used in this reaction. Typical  non-limiting examples of bases include  one or more of sodium hydroxide  potassium hydroxide  calcium hydroxide  lithium hydroxide  sodium carbonate  potassium carbonate  potassium tertiary-butoxide  sodium methoxide  calcium carbonate  sodium bicarbonate or potassium bicarbonate  pyridine or triethylamine. Typical  non-limiting examples of solvents that can be used in this step include water  C1-C6 alcohol  acetonitrile  tetrahydrofuran  ethyl acetate  hexane  toluene or a mixture thereof. Typical  non-limiting examples of alcohols include  methanol  ethanol  n-propanol  iso-propanol  n-butanol  t-butanol and so on. Compound of Formula (V) thus obtained may be purified or used as it is for the next steps.

Compound of Formula (VI)

In general  a compound of Formula (VI) is obtained by reacting a compound of Formula (V) with methanol in presence of a base.

A wide variety of bases can be used in this reaction. Typical  non-limiting examples of bases include  one or more of sodium hydroxide  potassium hydroxide  calcium hydroxide  lithium hydroxide  sodium carbonate  potassium carbonate  potassium tertiary-butoxide  sodium methoxide  calcium carbonate  sodium bicarbonate or potassium bicarbonate. Compound of Formula (VI) thus obtained may be purified or used as it is for the next steps.

Compound of Formula (VII)

In general  a compound of Formula (VII) is obtained by converting the nitro group in a compound of Formula (VI) to amino group.

The conversion of nitro group in compound of Formula (VI) to amino group can be accomplished by various means  such as for example  by reduction. The reduction can be achieved using Fe-HCl or Sn-HCl. The reduction can also be achieved using a typical hydrogenation reaction in presence of a transition metal catalyst and hydrogen gas. Typical  non-limiting  transition metal catalysts include those containing palladium  platinum  nickel  ruthenium and rhenium. An example  of such catalysts includes Raney Nickel. The hydrogenation reaction may be carried out in presence of a suitable solvent. Compound of Formula (VII) thus obtained may be purified or used as it is for the next steps.

Compound of Formula (VIII)

In general  a compound of Formula (VIII) is obtained by reacting a compound of Formula (VII) with benzylchloroformate in presence of a suitable solvent.

A wide variety of solvents can be used in this reaction. Typical  non-limiting examples of solvents that can be used in this step include C1-C6 alcohol  acetonitrile  tetrahydrofuran  ethyl acetate  hexane  toluene or a mixture thereof. Typical  non-limiting examples of alcohols include  methanol  ethanol  n-propanol  iso-propanol  n-butanol  t-butanol and so on. Compound of Formula (VIII) thus obtained may be purified or used as it is for the next steps.

Compound of Formula (I)

In general  a compound of Formula (I) is obtained by reacting a compound of Formula (VIII) with N-[(2S)-2-(acetyloxy)-3-chloropropyl]-acetamide.

This reaction may be carried out in presence of a suitable solvent. A wide variety of solvents can be used in this reaction. Typical  non-limiting examples of solvents that can be used in this step include C1-C6 alcohol  acetonitrile  tetrahydrofuran  ethyl acetate  hexane  toluene or a mixture thereof. Typical  non-limiting examples of alcohols include  methanol  ethanol  n-propanol  iso-propanol  n-butanol  t-butanol and so on.

In another general aspect  there is provided a process for preparation of a compound of Formula (IV) by reacting a compound of Formula (II) with a compound of Formula (III) in presence of a base and a solvent.

In general  a compound of Formula (IV) may be obtained by reacting a compound of Formula (II) and a compound of Formula (III) in presence of a base and a solvent. A wide variety of bases and solvents can be used in this reaction. Typical  non-limiting examples of bases include  one or more of sodium hydroxide  potassium hydroxide  calcium hydroxide  lithium hydroxide  sodium carbonate  potassium carbonate  potassium tertiary-butoxide  sodium methoxide  calcium carbonate  sodium bicarbonate or potassium bicarbonate  pyridine or triethylamine. Typical  non-limiting examples of solvents that can be used in this step include water  C1-C6 alcohol  acetonitrile  tetrahydrofuran  ethyl acetate  hexane  toluene or a mixture thereof. Typical  non-limiting examples of alcohols include  methanol  ethanol  n-propanol  iso-propanol  n-butanol  t-butanol and so on.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. For example  those skilled in the art will recognize that the invention may be practiced using a variety of different compounds within the described generic descriptions.

EXAMPLES

The following examples illustrate the embodiments of the invention that are presently best known. However  it is to be understood that the following are only exemplary or illustrative of the application of the principles of the present invention. Numerous modifications and alternative compositions  methods  and systems may be devised by those skilled in the art without departing from the spirit and scope of the present invention. The appended claims are intended to cover such modifications and arrangements. Thus  while the present invention has been described above with particularity  the following examples provide further detail in connection with what are presently deemed to be the most practical and preferred embodiments of the invention.

Example 1. : 1-(2 6-Difluoro-4-nitrophenyl)piperidin-4-one [Formula (IV)]

Method 1.

To a suspension of 100g of 3 4 5-trifluoronitrobenzene in iso-propanol (300ml) was added 104g of 4-piperidone-hydrochloride monohydrate. The reaction mass was treated with 142.7g of triethylamine slowly. The resulting mixture was stirred at 60°C till completion of the reaction. The reaction mass was diluted with water and the precipitate was filtered and washed with water. The solids were dried to yield 141g (97.5%) of 1-(2 6-Difluoro-4-nitrophenyl)piperidin-4-one with a HPLC purity of >99%.

Method 2.

To a suspension of 50g of 3 4 5-trifluoronitrobenzene in iso-propanol (250ml) was added 52g of 4-piperidone-hydrochloride monohydrate. To this 71.3g of triethylamine was added slowly. The resulting mixture was stirred at 60°C till completion of the reaction. Solvent was distilled out under vacuum at 40°C leaving behind a volume of 100ml of reaction mass. The reaction mass was diluted with water and the precipitate was filtered and washed with water. The solids were dried to yield 69.5g of 1-(2 6-Difluoro-4-nitrophenyl)piperidin-4-one with a HPLC purity of >99%.

Example 2. Preparation of 6-(2 6-difluoro-4-nitrophenyl)-1-oxa-6-azaspiro[2.5]-octane [Formula (V)]

Method 1.

28.4g of Potassium hydroxide was dissolved in a 1L mixture of acetonitrile-water (9:1). 111.7g of trimethylsulfoxonium iodide and 100g of 1-(2 6-Difluoro-4-nitrophenyl)-piperidin-4-one were added. The reaction mixture was warmed to 45°C and monitored to completion. The reaction mass was filtered and the filtrate was distilled under vacuum till about 300ml of the reaction mass was left behind. The reaction mass was then diluted with 900ml water and stirred for 0.5h at room temperature. The reaction mass was filtered to collect the solids. The wet solid was washed with water and dried to yield 98g (94%) of 6-(2 6-difluoro-4-nitrophenyl)-1-oxa-6-azaspiro[2.5]-octane with a HPLC purity of >99%.

Method 2.

14.2g of Potassium hydroxide was dissolved in a 0.5L mixture of acetonitrile-water (1:9). 53.7g of trimethylsulfoxonium iodide and 50g of 1-(2 6-Difluoro-4-nitrophenyl)-piperidin-4-one were added. The reaction mixture was warmed to 60°C and monitored to completion. The reaction mass was filtered to collect the solids. The wet solid was washed with water and dried to yield 50g (95%) of 6-(2 6-difluoro-4-nitrophenyl)-1-oxa-6-azaspiro[2.5]-octane with a HPLC purity of >96%.

Method 3.

9.96g of Potassium hydroxide was dissolved in 175ml mixture of acetonitrile-water (1:9). 37.6g of trimethylsulfoxonium iodide and 35g of 1-(2 6-Difluoro-4-nitrophenyl)-piperidin-4-one were added. The reaction mixture was warmed to 60°C and monitored to completion. The reaction mass was diluted with water and filtered to collect the solids. The wet solid was washed with water and dried to yield 35g (95%) of 6-(2 6-difluoro-4-nitrophenyl)-1-oxa-6-azaspiro[2.5]-octane with a HPLC purity of >96%.

Method 4.

1.4g of Potassium hydroxide was dissolved in 50ml mixture of t-butanol-water (1:4). 5.57g of trimethylsulfoxonium iodide and 5g of 1-(2 6-Difluoro-4-nitrophenyl)-piperidin-4-one were added. The reaction mixture was warmed to 50°C and monitored to completion. The reaction mass was filtered to collect the solids. The wet solid was washed with water and dried to yield 4.7g (89%) of 6-(2 6-difluoro-4-nitrophenyl)-1-oxa-6-azaspiro[2.5]-octane with a HPLC purity of >97%.

Method 5.

28.43g of Potassium hydroxide was dissolved in 1L mixture of iso-propanol-water (1:4). 111.75g of trimethylsulfoxonium iodide and 100g of 1-(2 6-Difluoro-4-nitrophenyl)-piperidin-4-one were added. The reaction mixture was warmed to 50°C and monitored to completion. The reaction mass was filtered at room temperature to collect the solids. The wet solid was washed with water and dried to yield 101g of 6-(2 6-difluoro-4-nitrophenyl)-1-oxa-6-azaspiro[2.5]-octane with a HPLC purity of >97%.

Example 3. Preparation of 1-(2 6-Difluoro-4-nitro-phenyl)-4-(methoxymethyl)- piperidin 4-ol [Formula (VI)].

5.55g of Sodium hydroxide was dissolved in 375ml of methanol. 75g of 6-(2 6-difluoro-4-nitrophenyl)-1-oxa-6-azaspiro [2.5]-octane was added to the solution and stirred at 45°C till completion of the reaction. Recovered ~225ml methanol under vacuum. The reaction was diluted with water. The pH was made neutral with dil. (~6N) HCl. The solids obtained were filtered and washed with water. The wet solid was dried to yield 82.2g 1-(2 6-Difluoro-4-nitro-phenyl)-4-(methoxymethyl) piperidin -4-ol with a HPLC purity of >98%.

Example 4. Preparation of Benzyl 3 5-difluoro-4-(4-hydroxy-4-(methoxymethyl)-piperidin-1-yl)-phenylcarbamate [Formula (VIII)]

Method 1.

300g of 1-(2 6-Difluoro-4-nitro-phenyl)-4-(methoxymethyl)piperidin-4-ol was dissolved in 3L of methanol. The solution was then hydrogenated at 14psi pressure in presence of 60g of Raney-Nickel catalyst at 40°C. On completion of the reaction the catalyst was filtered and the filtrate containing a compound of Formula (VII) was concentrated to thick slurry. 3L Ethyl acetate was charged to the slurry and stirred to get a clear solution. The organic layer was washed with water and dried over anhydrous sodium sulfate. 125g of sodium bicarbonate was added to the clear organic solution. To the heterogeneous reaction mass  423.4g of 50% Benzylchloroformate solution in Toluene was added slowly. The reaction mass was then stirred at 45°C till completion of the reaction. The reaction mixture was then cooled to room temperature and washed with water and brine. The organic layer was evaporated under vacuum to a volume of ~600ml. 1.2L Hexane was added to the slurry. The obtained solids were filtered and washed with hexane to obtain 372g (92%) of benzyl 3 5-difluoro-4-(4-hydroxy-4-(methoxymethyl)-piperidin-1-yl)-phenylcarbamate with a HPLC purity of >99%.

Method 2.

100g of 1-(2 6-Difluoro-4-nitro-phenyl)-4-(methoxymethyl)piperidin-4-ol was dissolved in 1L of ethyl acetate. The solution was then hydrogenated in presence of 10g of 10% Pd on Carbon dry catalyst at 50°C. On completion of the reaction the catalyst was filtered and the filtrate containing a compound of Formula (VII) was treated with 41.7g of solid sodium bicarbonate. 140g 50% Benzylchloroformate solution in Toluene was added slowly to the heterogeneous reaction mass. The reaction mass was then stirred at 45°C till completion of the reaction. The reaction mixture was then cooled to room temperature and washed with water and brine. The organic layer was evaporated under vacuum leaving behind 100ml solvent. 250ml Hexane was added to the slurry. The obtained solids were filtered and washed with hexane  dried to obtain 120g (89%) of benzyl 3 5-difluoro-4-(4-hydroxy-4-(methoxymethyl)-piperidin-1-yl)-phenylcarbamate with a HPLC purity of >99%.

Example 5. Preparation of (5S)-N-{3-[3 5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide [Formula (I)]

20g of [3 5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-carbamic acid benzyl ester was dissolved in 200ml tetrahydrofuran at room temperature. 11.8g of Lithium t-butoxide was then added to the reaction mass. After stirring for about 10min the reaction mass was cooled to 0°C and 3.15g of methanol was added to it. This was followed by addition of 19g of N-[(2S)-2-(acetyloxy)-3-chloropropyl]acetamide. The reaction mass was stirred for 18h at 10°C. 200ml water was added under stirring. The pH was made neutral and the reaction mass was extracted with methylene chloride. The extracts were concentrated under reduced pressure and the residue obtained was crystallized from a mixture of acetone-hexane. The solids obtained were refluxed in ethyl acetate for 1h and cooled to room temperature. The reaction mass was then filtered to collect the solids. The solids were washed with ethyl acetate and dried to yield 11.9g (75.5%) of (5S)-N-{3-[3 5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide with a HPLC purity of >98%.

About 4.5g of [3 5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-carbamic acid benzyl ester was recovered from the acetone-hexane filtrates.

Example 6. Preparation of 1-(2 6-Difluoro-4-nitro-phenyl)-4-(methoxymethyl) piperidin-4-ol [Formula (VI)] from 1-(2 6-Difluoro-4-nitrophenyl)piperidin-4-one [Formula (IV)].

9.85g of Potassium hydroxide was dissolved 250ml of methanol. 27.9g trimethylsulfoxonium iodide and 25g of 1-(2 6-Difluoro-4-nitrophenyl)piperidin-4-one were added. The reaction mass was warmed to 50°C and monitored to completion. The reaction mass was treated with charcoal and filtered. The filtrate was evaporated to leave behind about 1 volume of solvent. The reaction was then diluted with 250ml water. The pH was made neutral with dil. HCl. The solids obtained were filtered and washed with water. The wet solid was dried to yield 27.5g (93.5%) of 1-(2 6-Difluoro-4-nitro-phenyl)-4-(methoxymethyl) piperidin-4-ol with a HPLC purity of >96%.

WE CLAIM:

1. A process for preparing a compound of Formula (I)

comprising 

(a) reacting a compound of Formula (IV) with trimethylsulfoxonium iodide or trimethylsulfonium iodide in presence of a base and a solvent to obtain a compound of Formula (V):

(b) reacting a compound of Formula (V) with methanol in presence of a base to obtain a compound of Formula (VI)

(c) reducing the compound of Formula (VI) to obtain a compound of Formula (VII)

(d) reacting a compound of Formula (VII) with benzylchloroformate in presence of a solvent to obtain a compound of Formula (VIII)

(e) reacting a compound of Formula (VIII) with N-[(2S)-2-(acetyloxy)-3-chloropropyl]-acetamide to obtain the compound of Formula (I).

2. The process according to Claim 1  wherein the base used is one or more of sodium hydroxide  potassium hydroxide  calcium hydroxide  lithium hydroxide  sodium carbonate  potassium carbonate  potassium tertiary butoxide  sodium methoxide  calcium carbonate  sodium bicarbonate or potassium bicarbonate  pyridine or triethylamine.

3. The process according to Claim 1  wherein the solvent used is water  C1-C6 alcohol  acetonitrile  tetrahydrofuran  ethyl acetate  hexane  toluene or a mixture thereof.

4. The process according to Claim 1  wherein the reduction in step (c) is achieved in presence of a transition metal catalyst.

5. The process according to Claim 4  wherein the transition metal is one or more of palladium  platinum  nickel  ruthenium  and rhenium.

6. The process according Claim 1  wherein the reduction in step (c) is achieved using Fe-HCl or Sn-HCl.
7. A process for preparing a compound of Formula (I)

comprising 

(a) reacting a compound of Formula (IV) with trimethylsulfoxonium iodide or trimethylsulfonium iodide in presence of potassium hydroxide and water-acetonitrile or water-tertiary butanol  to obtain a compound of Formula (V):

(b) reacting a compound of Formula (V) with methanol in presence of a sodium hydroxide or potassium hydroxide to obtain a compound of Formula (VI)

(c) reducing a compound of Formula (VI) in presence of Raney-Nickel catalyst to obtain a compound of Formula (VII)

(d) reacting a compound of Formula (VII) with benzylchloroformate in presence of a tetrahydrofuran or ethyl acetate to obtain a compound of Formula (VIII)

(e) reacting the compound of Formula (VIII) with N-[(2S)-2-(acetyloxy)-3-chloropropyl]acetamide to obtain the compound of Formula (I).

8. The process according to any of the preceding Claims 1-7  wherein the compound of Formula (IV) is obtained by reacting a compound of Formula (II) with a compound of Formula (III) in presence of a base and a solvent.

9. The process according to Claim 8  wherein the base is one or more of sodium hydroxide  potassium hydroxide  calcium hydroxide  lithium hydroxide  sodium carbonate  potassium carbonate  calcium carbonate  sodium bicarbonate or potassium bicarbonate  pyridine or triethylamine.

10. The process according to Claim 8  wherein the solvent used is water  C1-C6 alcohol  acetonitrile  tetrahydrofuran  ethyl acetate  hexane  toluene or a mixture thereof.

Dated this 7th day of July 2011.
(Dr. Mandar Kodgule)
Associate Vice President  Global IP
Wockhardt Limited