Zolmitriptan is an important drug for the treatment of migraine.

The process involves preparation of the above said compound of the formula I using novel intermediate of the formula II

BACKGROUND OF INVENTION In the literature on, ly two processes are available to prepare (S)-4- (4-aminobenzyl)-2-oxazolidinone of the formula (I).

In the first route disclosed in WO 9118871 (corresponding to US patent No 5466699), the process for the preparation of compound of formula (I) comprises (i) esterification of (S)-4-nitro-phenylalanine to give (S)-methyl-4-nitro phenyl alanate of the formula (III).

(2) Reducing the compound of the formula (III) with sodiumborohydride to give (S)-4-nitrophenylalanilol of the formula (IV). (3) Cyclising the compound of the formula (IV) using phosgene to give (S)-4- (4-nitrobenzyl) 1, 3-oxazolidinone of the formula (V).

(4) Hydrogenating the compound of the formula (V) with 5% Pd-C to give (S) -4- (Aminobenzyl)-1, 3-oxazolidinone of the formula (I).

The main draw backs of the process are: 1. Yield reported in the step No. 3 is only 41%.

2. Process involves use of phosgene which is dangerous and not preferable for using the process on a commercial scale.

3. Overall yield from step (1) to step (4) is only 17%.

The second route disclosed in [WO 97/06162, WO 97/06163] which comprises of following steps: a) Forming a carbamate from methyl-4-nitro-(L)-phenylalanate HCI represented by the formula (III) by the reaction of sodium carbonate (or) sodium hydrogen carbonate and n-butylchloroformate to give methyl (S)-N-butoxycarbonyl-4-nitrophenyl alana. te of the formula (VI). b) Reduction of the nitro group in the compound of the formula (VI) to give methyl (S)-N-butoxycarbonyl-4-aminophenylalanate of the formula (VII). c) Reduction of the methyl ester group (-C02CH3) in the compound of the formula (VII) to give (S)-N-butoxycarbonyl-4-aminophenylalaninol of the formula (VIII). d) Ring closure of the compound of the formula (VIII) with 30% sodium methoxide in methanol to give (S)-4- (Aminobenzyl)-1, 3-oxazolidinone of the formula (I).

This process involves relatively more expensive reagent butyl chloro formate in step (a) and step (d) needs extremely dry conditions and involves use of anhydrous sodium methoxide. These critical process parameters are very difficult to maintain consistently in a process plant, more so while taking scale up on commercial batches. Yields are not mentioned in the patent for any of the stages mentioned. However, we have found that experimentally only 20-25% overall yields are realized.

Considering the importance gained by Zolmitriptan for the treatment of migraine for which the compound of the formula I is an important intermediate there is a great need for developing a simple inexpensive and safe method for the commercial scale preparation of (S)-4- (4- aminobenzyl)-2-oxazolidinone of the formula I Therefore the main objective of the present invention is to provide an improved process for the preparation of (S)-4- (4-aminobenzyl)-2- oxazolidinone (I) which is inexpensive, salable on a commercial scale, high yielding (40% overall yield) and safe.

According to another objective of the present invention is to provide an improved process for the preparation of oxazolidinone of formula (I) by replacing the highly toxic phosgene with simple non-toxic reagents like dialkyl carbonates in the cyclization step thereby making the process safe and user friendly.

Yet another objective of the present invention is to provide an improved process for the preparation of (S)-4- (4-aminobenzyl)-2-oxazolidinone of the formula (I) starting from (S)-4-Nitrophenyl-alaninol of the formula (IV).

Still another objective of the present invention is to provide an improved process for the preparation of oxazolidinone of the formula (I) by carrying out the aromatic nitro group reduction in the early part of the synthesis there by producing a novel intermediate.

Another objective of the present invention is to provide an improved process for the preparation of the oxazolidinone of the formula (I) by avoiding an additional step involving formation of a carbamate in the synthesis thereby reducing the number of steps and improving the overall yields.

SUMMARY OF INVENTION Keeping in view of the difficulties in commercialization of the processes disclosed in the above mentioned prior art patents, we aimed our research work to develop a simple and convenient process for the preparation of the oxazolidinone of the formula (I) which can be utilized for the preparation of zolmitriptan of the formula (A).

In our sustained research to develop a simple process for the preparation of the oxazolidinone of the formula (I), we observed that a promising approach for developing such a process would be to. a) Avoid the usage of phosgene in the ring formation step.

b) Reduce the nitro group present in the compound of the formula (IV) with appropriate reducing agent before the cyclisation step. c) Use of dialkylcarbonates like dimethyl carbonate, diethyl carbonate in ring formation step.

Accordingly we focused our research on the above mentioned directions.

Following the above directions we are successful to develop an improved process for the preparation of oxazolidinone of the formula (I).

Accordingly, we observed that the ring formation step can be carried out in the presence of an amino group present on benzene ring of compound of the formula (II).

We also found further that dialkyl carbonates used in the ring formation step gave better yields than the phosgene method (30-35% higher overall yield).

Accordingly, the present invention provides an improved process for the preparation of (S)-4- (4-aminobenzyl)-2-oxazolidinone of the formula (I) which comprises:

(i) Preparing the 4-nitro-(S)-phenylalaninol of the formula (IV) by conventional methods.

(ii) Reducing the nitro compound of formula (IV) by hydrogenation in the presence of a metal catalyst in alcoholic solvents under pressure at a temperature in the range of 25-80°C, to produce a novel intermediate of the formula (II).

(iii) Isolating the reduced product of the formula (II) by filtration of catalyst and followed by distillation of the solvent.

(iv) Reacting the compound of formula (II) obtained with dialkyl carbonate at a temperature in the range of 80-200 °C.

(v) Isolating the oxazolidinone of the formula (I) by distilling off the unused dialkyl carbonate at a temperature below its boiling point and (vi) Recrystallizing the oxazolidinone of formula (I) from an alcoholic solvent We have described and claimed the novel intermediate of the formula II in a separate application which is being filed simultaneously with this application The 4-nitro-(S)-phenylalaninol of formula (IV) in the step (i) may be prepared by following the method described in the US patent No. 5466699.

For example 4-nitro-(S)-phenylalaninol of formula (IV) may be prepared as follows : Esterification of (S)-4-nitro phenylalanine with methanol, and thionyl chloride at-10°C yields (S)-methyl-4-nitro phenylalanate hydrochloride of the formula (III).

Compound of the formula (III) on reduction with sodium borohydride in aqueous ethanol medium yields compound of the formula (IV). The metal catalyst used in step (ii) may be Raney nickel, Palladium/carbon, Platinum/carbon, preferably Raney nickel or 5% palladium on carbon. The amount of catalyst employed may range from 5% to 20% by weight. The reduction step may also be carried out by using metal/acid eg. SnCl2/HCl, Fe/HCI and the like.

The alcoholic solvent used may be selected from methanol, ethanol, isopropanol and the like.

The solvent used in step (ii) may be selected from methanol, ethanol, isopropanol, etc. , preferably methanol. The hydrogen pressure used in case of catalytic hydrogenation may be in the range of 20-80 psi preferably in the range of 40-60 psi. The temperature of the hydrogenation may be preferably in the range of 30-40°C.

The dialkyl carbonates used in step (iv) may be selected from dimethyl carbonate, diethylcarbonate, diisopropyl carbonate, dibutyl carbonate, preferably dimethyl or diethylcarbonate. The temperature of the reaction in cyclization step of (iv) may be preferably in the range of 90-130°C.

The solvent used in recrystallization step (vi) may be selected from methanol, ethanol or isopropanol.

A particularly preferred reaction scheme for the preparation of the compound of the formula (I) is shown below : NH/'', NH nit2 (i) Hydrogen, 5% Pd-C NH2 'r, °2 CH2OH (ii) Methanol, RT H2N CH2OH 2 (IV) (If) 0 H N-C Diethyl carbonate H2N) K2CO3 0 H2 N (I)

The details of the invention are given in the Examples given below which are provided for illustration only and therefore these examples should not be construed to limit the scope of the invention.

Example 1 : The preparation of S-4- (4-Aminobenzyl)-2-oxazolidinone A) The preparation of (S)-2-amino-3- (4-aminophenyl) propanol /,, ,, NH2 <""gNH2 (i) Hydrogen, 5% Pd-C I 02N \ CH20H Methanol, RT H2N CH20H C9H12N2O3 C9H14N2O M. W: 196.0 M. W: 166.0 Raw materials Qty 1. (S)-2-Amino-3- (4-nitro phenyl) propanol-10. 0 Kg 2. Methanol-111. 0 Kg 3. 5% Palladium carbon (50% water wet) -2. 0 Kg 4. Ethyl acetate-24.0 Kg 5. n-Hexane-20.0 Kg 6. Hydrogen-as required Procedure Charge to the reactor the methanolic solution of (S)-2-Amino-3- (4-nitro phenyl)-propanol, and 5% palladium carbon catalyst and hydrogenate at about 60 psi of hydrogen at room temperature. On completion, filter off the catalyst through filter aid and wash with methanol. The methanol solution of novel (S)-2-Amino-3- (4-aminophenyl) propanol of the formula (II) is completely distilled under vacuum.

Charge the mixture of ethyl acetate and n-Hexane to the residue. After cooling the solution to 10°C for about 2 hours, filter and wash the filtered product with n-hexane and dry it about 50°C in vacuum (7.6 Kg, 89.5% ; mp 108-112°C) HPLC purity - 99%.

Analysis: C9H14N2O ; molecular weight: 166.0 IR spectrum-KBr disc Absence of-N02 NH2 at 3307 and 3368 cm-1 UV spectrum-Methanol Bmax at 238.75 nm % min at 293.15nm 'H NMR (DMSO-d6) (ppm) 2.15-2. 30 and 2. 40-2. 55 (m, 2H, Ph-CH2) 2.60-2. 85 (m, lH, CH-NH2) 3.05-3. 20 and 3.20-3. 40 (m, 2H, CH2-OH) 6.40-6. 55 (d, 2H, Ar-protons) 6.75-6. 95 (d, 2H, Ar-protons) 13C NMR (DMSO-d6) 40.0 (Ar. CH2) 54.6 (-CH-NH2) 65.6 (-CH2-OH) (Ar. Carbon) B) The preparation of (S)-4- (4-aminobenzyl)-2-oxazolidinone. 0 LJ N NH2 Diethyl carbonate N-C r,...,, Potassium carbonate-r HzN H2N

C9H14N2O C10H12N202 M. W: 166.0 M. W: 192.0 Raw materials Qty 1. (S)-2-Amino-3- (4-amino phenyl) propanol-7. 6Kg 2. Diethyl carbonate-13.5 Kg 3. Potassium carbonate-0. 633 Kg 4. Methanol-35. 0 Kg 5. isopropanol-9. 5Kg Procedure Charge into reactor (S)-2-Amino-3- (4-amino phenyl)-propanol obtained by the process explained in step (A), diethyl carbonate and potassium carbonate at 135°C. Distill off ethanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature charge methanol and filter salts through filter aid and wash with methanol. Distill off the filtered methanol completely under vacuum and charge isopropanol to the residue. Filter through filter aid and wash the product ( (S)-4- (4- aminobenzyl)-2-oxazolidinone) with isopropanol. Dry at 50°C in vacuum (6.85 Kg, 76.7%, mp 95-100OC).

Analysis: CioHi2N202, molecular weight: 192.0 IR spectrum: KBr, Lactone: 1759 cm-1 tHNMR and 13CNMR were consistent with the proposed structure.

Example 2 : . 1, 11 NH2..."NH2 (i) Iron l Conc. HCI. 02N CH2OH 95% ethanol, reflux H2N CH20H 2

CgH2N203 C9H14N20 M. W: 196.0 M. W: 166.0 A) The preparation of (S)-2-amino-3- (4-aminophenyl) propanol.

Raw materials Qty 1. (S)-2-Amino-3- (4-nitro phenyl) propanol-10. OKg 2. Iron filings-30. 6 Kg 3.95% Ethanol-35. 0 Kg 4. Conc. Hydrochloric acid-0.610 Kg 5. Ethyl acetate-20.0 Kg 6. n-Hexane-16.0 Kg 7. DM water-10 Kg Procedure Charge into reactor (S)-2-Amino-3- (4-nitrophenyl)-propanol, 95% ethanol, iron filings, DM water and conc. Hydrochloric acid at room temperature.

Reflux the reaction mass for three hours. After cooling the reaction mass to room temperature filter off iron through filter aid and wash thoroughly with 95% ethanol. Distill off the ethanol solution of (S)-2-amino-3- 4 (aminophenyl) propanol completely under vacuum.

Charge the mixture of ethyl acetate and n-Hexane to the residue. After cooling the solution to 10°C for about 2 hours, filter and wash the filtered product with n-Hexane and dry it about 50°C in vacuum (6.2 Kg, 73.0%, mp : 107-111°C) HPLC purity: 98.7% Analysis : C9Hl4N20, molecular weight: 166.0 IR, 1HNMR and 13CNMR were consistent with the proposed structure.

B) The preparation of (S)-4- (4-aminobenzyl)-2-oxazolidinone. H p '"NH2 Y'''''' (r Dimethyl carbonate J : y ; ZL" 0 H2N CH20H Potassium carbonate H2N+/

CgHi4N20 C10H12N2O2 M. W: 166.0 M. W: 192.0 Raw materials Qty 1. (S)-2-Amino-3- (4-aminophenyl) propanol-6. 2 Kg 2. Dimethyl carbonate-8. 4 Kg 3. Potassium carbonate-0.520Kg 4. Methanol-30. 0 Kg 5. Isopropanol-7. 5 Kg Procedure Charge into reactor (S)-2-Amino-3- (4-aminophenyl) propanol prepared by the process explained in step (A), dimethyl carbonate and potassium carbonate at 115-120°C. Distill off methanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature charge methanol and filter salts through filter aid and wash with methanol.

Distill off filtered methanol completely under vacuum and charge isopropanol to the residue. Filter and wash the product [(S)-4- (4-aminobenzyl)-2- oxazolidinone] with isopropanol. Dry at 50°C In vacuum (5.5 Kg, 75.0%, mp 95-100OC) Analysis: ClOH12N202, molecular weight: 192.0 IR, 1HNMR and 13CNMR were consistent with the proposed structure.

Example 3 : A) The preparation of (S)-2-amino-3- (4-aminophenyl) propanol. "....-NH, "... H, SnC122H20/Conc. HCI 1) 0 02N CH20H H2N CH20H

CgH12N203 C9H14N20 M. W: 196.0 M. W: 166.0 Raw materials Qty 1. (S)-2-Amino-3- (4-amino phenyl) propanol-10. OKg 2. Stannous chloride dihydrate-61.0 Kg 3. Conc. Hydrochloric acid-178.0 Kg 4.50% sodium hydroxide solution-250 Kg 5. Ethyl acetate-20.0 Kg 6. n-Hexane-15.0 Kg 7. DM water-500 L Procedure Charge into reactor conc. Hydrochloric acid and stannous chloride dihydrate at room temperature. Cool to 0°C. Add (S)-2-amino-3- (4-nitrophenyl) propanol lot wise slowly at 0-5°C during two hours. Bring reaction mass to room temperature and maintain for two hours at 25-35°C. Charge 200 L DM water to the reactor and adjust pH to 12-13 with 50% sodium hydroxide solution. Filter the separated mass through filter aid. Suspend the filtered solid into reactor and charge ethyl acetate and extract for 30 minutes. Filter again through filter aid and water wash ethyl acetate layer with DM water till pH of last washing is neutral. Concentrate ethyl acetate solution of (S)-2-Amino-3- (4-aminophenyl)-propanol, to a residual quantity of 15-20 Kgs. Cool to room temperature and n-Hexane to the residue. After cooling

the solution to 10°C for about 2 hours, filter and wash the filtered product with n-Hexane and dry it about 50°C in vacuum (5.1 Kg, 60.0%, mp: 108- 110°C) HPLC purity 99.1% Analysis: C9H14N20, molecular weight: 166.0 IR, 1HNMR and 13CNMR were consistent with the proposed structure.

B) The preparation of (S)-2-amino-3- (4-aminophenyl) propanol. H 0 H H 1°l /..,, NH2 ..,, NwC Dimethyl carbonate I I zozo H2N CH20H Potassium carbonate H2N

C9H14N2O C10H12N2O2 M. W: 166.0 M. W: 192.0 Raw materials Qty 1. (S)-2-Amino-3- (4-aminophenyl) propanol-5. 1 Kg 2. Dimethyl carbonate-9.1 Kg 3. Potassium carbonate-0.42 Kg 4. Methanol-25. 0 Kg 5. Isopropanol-6. 5 Kg Procedure Charge into reactor (S)-2-Amino-3- (4-aminophenyl) propanol obtained by the process explained in step (A), dimethyl carbonate and potassium carbonate at 135°C. Distill off methanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature, charge methanol and filter salts through filter aid and wash with methanol.

Distill off filtered methanol completely under vacuum and charge isopropanol to the residue. Filter and wash the product with isopropanol. Dry at 50°C under vacuum (4.5 Kg, 76.0%, mp 95-100°C)

Analysis : C, oHl2N202, molecular weight: 192.0 IR, tHNMR and CNMR were consistent with the proposed structure.

Example 4 A) The preparation of (S)-2-amino-3- (4-aminophenyl) propanol. /\/""', NH2 Raney Nickel 02Nw CH20H Ethanol 2 02N

C9H12N203 CgH14N20 M. W: 196.0 M. W: 166.0 Raw materials Qty 1. (S)-2-Amino-3- (4-nitrophenyl) propanol-10. OKg 2. Raney Nickel-0. 650 Kg 3. Anhydrous ethanol-22. 0 Kg 4. Ethyl acetate-24.0 Kg 5. n-Hexane-20.0 Kg Procedure Charge into reactor ethanolic solution of (S)-2-Amino-3- (4-aminophenyl) propanol and Raney nickel catalyst and hydrogenate at about 60 psi of hydrogen at room temperature. On completion, filter off catalyst through filter aid and wash with ethanol. The ethanol solution of (S)-2-Amino-3- (4- aminophenyl) propanol of the formula (II) is completely distilled under vacuum. Charge mixture of ethyl acetate and n-hexane to the residue.

After cooling the solution to 10°C for about 2 hours, filter and wash the filtered product with n-Hexane and dry it about 50°C in vacuum (7.5 Kg, 88.3%, mp: 107-111°C)

Analysis: C9H14N20, molecular weight: 166.0 IR,'HNMR and 13CNMR were consistent with the proposed structure.

B) The preparation of (S)-4- (4-aminobenzyl)-2-oxazolidinone. H 0 "rNH2 <"Ns ll Dimethyl carbonate. I I _ CH20H Potassium carbonate'10

C9H14N2O C10H12N2O2<BR> <BR> <BR> M. W : 166.0 M. W : 192.0 Raw materials Qty 1. (S)-2-Amino-3- (4-aminophenyl) propanol-7. 5 Kg 2. Dimethyl carbonate-13.3 Kg 3. Potassium carbonate-0.62 Kg 4. Methanol-35. 0 Kg 5. Isopropanol-9. 4 Kg Procedure Charge into reactor (S)-2-Amino-3- (4-aminophenyl) propanol obtained by the process described in step (A), dimethyl carbonate and potassium carbonate at 135°C. Distill off methanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature charge methanol and filter salts through filter aid and wash with methanol.

Distill off filtered methanol completely under vacuum and charge isopropanol to the residue. Filter and wash the prod uct [ (S)-4- (4-ami nobenzyl)-2- oxazolidinone.] with isopropanol. Dry at 50°C under vacuum (6.75 Kg, 76.7%, mp 95-100°C) Analysis: CloHl2N202 molecular weight: 192.0 IR, 1HNMR and 13CNMR were consistent with the proposed structure.

Advantages of the process of the present invention w The process is more efficient in terms of yields. 40% overall yields are realized for the production of compound of the formula (I) starting from compound of the formula (III) when compared to 17% reported in literature.

The process does not involve use of toxic reagents like phosgene which is all the more difficult when operating on a commercial scale.

The process does not involve additional steps as preparation of a carbamate as is the case with the process employing butyl chloroformate.

'The process also avoids employing extremely dry conditions required while handling sodium methoxide as in the butyl chloroformate process 'The process results in providing a novel intermediate of the formula II 'The process is commercially viable.