Title of Invention

NOVEL PROCESS FOR THE PREPARATION OF (S)-4-(4-AMINOBENZYL)2-OXAZOLIDINONE

Abstract The invention disclosed in this application relates to an improved process for the preparation of the oxazolidinone of formula (I). It comprises (i) Preparing the 4-nitro-(S)-phenylalaninol of formula (IV) by conventional methods, (ii) Reducing the nitro compound of formula (IV), (iii) Reacting the resulting novel compound of the formula (II) with dialkyl carbonate at a temperature in the range of 80-200°C. to produce the compound of the formula I. The compound of the formula I is useful for the preparation of zolmitriptan which is an important drug for the treatment of migraine.
Full Text INTRODUCTION
The present invention relates to an improved process for the preparation of
(S)-4-(4-aminobenzyl)-2-oxazoliclinone. (S)-4-(4-aminobenzyl)-2-
Qxazolidinone prepared by the process of the present Invention has the formula I given below and is useful for the preparation of zolmitriptan.

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 only two processes are available to prepare (S)-4-(4-aminobenzyl)-2-oxazolidinone of the formula (I). In the first route disclosed in WO 9118897 (corresponding to US patent No 5466699), the process for the preparation of compound of formula (I) comprises


esterification of (S)-4-nitro-phenylalanme 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) Cydising the compound of the formula (IV) using phosgene to give (S)-
4-(4-nitrobenzyl)l,3-oxazolidinone of the formula (V).

(4) Hydrogenating the compound of the formula (V) with 5% Pd-C to give
(S)-4- (Aminobenzyl)-l,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)-phenYlatanate 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 alanate 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 (- CO2CH3) 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)-l,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, scalable 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 dialkyi carbonates in the cydization 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 aaent before the cydisation 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 dialkyi 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 dialkyi carbonate
at a temperature in the range of 80-200 °C. (v) Isolating the oxazolidinone of the formula (I) by distilling off the unused

dialkyi 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. SnCb/HCI, Fe/HCI and the like.
The alchoholic 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 dialkyi 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 cydization 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.



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-Annino-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 - NO2
NH2 at 3307 and 3368 cm-1
UV spectrum - Methanol
λmax at 238.75 nm

λmin at 293,15nm 1H NMR (DMSO - ds) (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-de)
40.0 (Ar.CHz )
54.6 (-CH - NH2)
65.6 (-CH2 - OH) (Ar. Carbon)

B) The preparation of (S)-4- (4-aminobenzyl)-2-oxazolidinone.

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 95-100°C).
Analysis : C10H12N2O2, molecular weight : 192.0
IR spectrum : KBr, Lactone : 1759 cm-1
1HNMR and 13CNMR were consistent with the proposed structure.


Charge into reactor (S)-2-Amino-3-(4-nitrophenyl)-propanol, 95% ethanol,
iron filings, DM water and cone. 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%


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 95-100°C)
Analysis : C10H12N2O2, molecular weight : 192.0
IR , 1HNMR and 13CNMR were consistent with the proposed structure.


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 C9H14N2O, molecular weight : 166.0 IR , 1HNMR and 13CNMR were consistent with the proposed structure.

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 : C10H12N2O2, molecular weight : 192.0
IR , ^HNMR and ^-^CNMR were consistent with the proposed structure.

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 : C9H14N2O, molecular weight : 166.0
IR , 1HNMR and 13CNMR were consistent with the proposed structure.

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 product[(S)-4-(4-aminobenzyl)-2-oxazolidinone.] with isopropanol. Dry at 50°C under vacuum (6.75 Kg, 76.7%, mp 95-100°C) Analysis : C10H12N2O2, molecular weight : 192.0 IR , ^HNMR and ^^CNMR were consistent with the proposed structure.

Advantages of the process of the present invention
• 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



We Claim
1. An improved process for the preparation of (S)-4-(4-aminobenzyl)-2-oxazolidinone of the formula 1 .
which comprises
(i) Preparing the 4-nitro-(S)-phenylalaninol of 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 formula (II) by filtration of catalyst and
followed by distillation of solvent, (iv) Reacting the novel compound of the formula (II) with dialkyi carbonate at
a temperature in the range of 80-200 °C.

(v) Isolating the oxazolidinone of the formula (I) by distilling off dialkyi carbonate at a temperature below its boiling point.

(vi) Recrystallising the oxazolidinone of the formula (I) above from an alcoholic solvent.
2. An improved process as claimed in claim 1 wherein the dialkyi carbonates used in step (iv) is selected from dimethyl carbonate, diethyl carbonate, diisopropyl carbonate, dibutyl carbonate, preferably dimethyl or diethylcarbonate.
3. An improved process as claimed in claims 1 to 2 wherein the temperature of the reaction in cyclization step of (iv) ranges from 90-130°C.
4. An improved process as claimed in claims 1 to 3 wherein the solvent used in recrystallization step (vi) is selected from methanol, ethanol or isopropanol.

5. An improved process for the preparation of (S)-4-(4-aminobenzyl)-2-oxazolidinone of the formula 1 as defined in claim substantially as herein described with reference to the Examples 1-4,


Documents:


Patent Number 198915
Indian Patent Application Number 29/CHE/2003
PG Journal Number 30/2009
Publication Date 24-Jul-2009
Grant Date 17-Feb-2006
Date of Filing 13-Jan-2003
Name of Patentee M/S. NATCO PHARMA LTD
Applicant Address NATCO HOUSE ROAD NO 2 BANJARA HILLS HYDERABAD 500 033
Inventors:
# Inventor's Name Inventor's Address
1 AMALA KOMPELLA NATCO PHARMA LTD NATCO HOUSE ROAD NO 2 BANJARA HILLS HYDERABAD 500 033
2 THUNGATHURTHY SRINIVASA RAO NATCO PHARMA LTD NATCO HOUSE ROAD NO 2 BANJARA HILLS HYDERABAD 500 033
3 ADIBHATLA KALI SATYA BHUJANGA RAO NATCO PHARMA LTD NATCO HOUSE ROAD NO 2 BANJARA HILLS HYDERABAD 500 033
4 VENKAIAH CHOWDARY NANNAPANENI NATCO PHARMA LTD NATCO HOUSE ROAD NO 2 BANJARA HILLS HYDERABAD 500 033
PCT International Classification Number A61K31/42
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA