Field of the invention
The present invention relates to an improved process for the preparation of oxazolidine derivative of formula (I)

Compound of formula (I) is useful for preparing anticancer compounds having taxane skeleton such as paclitaxel, docetaxol etc.
Background of the invention
The taxane families of terpenes are considered as a potent anti-tumor chemotherapeutics having a broad spectrum of anti-leukemia and anti-tumor activity. Accordingly, many concems have been focused on this compound in both the areas of biology and chemistry. It is known that oxazolidine derivatives have been coupled with taxane derivative to prepare paclitaxel.
US patent 5,476,954 discloses oxazoUdine derivative of formula (I) where the process disclosed requires reacting dimethoxyalkane with a phenyUsoserine ester derivative. The process involves more number of reaction steps for the preparation of compound of formula (I). The chemicals like sodium adize and di-n-butylboron triflate used in this process are difficult to handle at plant scale. Reaction scheme of the process disclosed in said patent is described in Scheme 1.


us patent 5,292,921 discloses the process for the enantioselective preparation of phenylisoserine derivative of formula (d) wherein the starting material is phenyl glycine and involves Swem oxidation, carried out under cryogenic conditions in presence of oxalyl chloride/dimethyl sulphoxide mixture, which is quite cumbersome and results in at least 5% of racimisation as described in Scheme-2.

Said process starts with different starting material which results in increased reaction steps. US patent 6,433,180 granted to the same group of inventors discloses the process of preparation of isomer (i.e. 4S, 5S) of compound of formula (I) which is prepared by using compound of formula (d) of US 5,292,921 patent. The above processes give comparatively lower yield, and are difficult to operate on the plant scale production.

To overcome these drawbacks we developed improved process which is highly steroselective, easy to operate on the plant scale with high yield.
Objective of Invention
The main objective of the present invention is to provide an improved process for the commercial/bulk preparation of the compound of formula (I) which is useful for preparing anticancer compounds having taxane skeleton such as pacUtaxel, docetaxol.
Another objective of the present invention is the use of 2,2,6,6-tetramethylpiperidine-N-oxide (herein after abbreviated as TEMPO) as oxidizing agent in presence of hypochlorite such as sodium hypochlorite (NaOCl) to replace Swem oxidation which is carried out in presence of oxalyl chloride/dimethyl sulphoxide mixture. TEMPO is user friendly chemical and reduces the volume of the reaction and therefore enabling performance of big batch at plant scale.
The further objective of the present invention is to provide a process for the preparation of compound of formula (I) with high yield and smaller time cycle.
Summary
Accordingly the present invention relates to an improved process for preparing a compound of the formula (I)

which comprises: (i) Protecting the amino group of phenyl glycinol by dissolving it in a solvent in
presence of a base at a temperature in the range of 20-40 **C and treating with a
reagent for introducing t-butoxycarbonyl group, to obtain the compound of
formula (II). (ii) Oxidizing compound of formula (II) in presence of TEMPO, halogenated alkali
metal, hypochlorite such as NaOCl and base in a aqueous/solvent mixture.

Addition of the obtained carbonyl intermediate as a solution in a solvent to vinyl magnesium halide, Grignard solution in a solvent at 15 °C to 40 °C for a duration of 30 minutes to -3 hours to obtain a compound of formula (III).
(iii) Protecting the hydroxyl group by dissolving compound of formula (III) in an organic solvent, followed by addition of a protecting reagent at a temperature in the range of 20 **C to 40 °C and a catalyst, and further heating the reaction mixture at a temperature in the range of 50-105 **C, for a duration of 1-5 hours to obtain the compound of formula (IV).
(iv) Optionally doing the column purification by dissolving the compound of formula (IV) in a polar solvent and eluting in presence of ether initially and later with increasing concentrations of ethyl acetate in ether.
(v) Oxidizing compound of formula (IV) by means of an alkali metal periodate, in the presence of a catalyst and base. The reaction is carried out in aqueous/organic medium at a temperature in the range of 20 °C to 40 °C.


Detailed Description
The present invention relates to a novel process for the preparation of oxazohdine derivative of formula (I)

which is useful for preparing anticancer compounds having taxane skeleton such as paclitaxel, docetaxol etc.
The process for preparing a compound of the formula (I) comprises: (i) Dissolving phenyl glycinol in polar solvent, to this base such as sodium hi carbonate, potassium bi carbonate is added at a temperature in the range of 10 °C to 60 ^C and the reaction mixture is stirred for a time period of 10 minutes to 60 minutes, A solution of t-butoxycarbonyl group such as Boc anhydride in polar solvent is slowly added to reaction mass over a period of 20-50 minutes followed by stirring of reaction mixture at a temperature in the range of 20-40 **C for 20 minutes to 40 minutes. After completion of reaction, water is added to the reaction mass. The organic layer is separated and concentrated to the minimum level, to this ether is added stirred for 10 -50 minutes, filtered and dried at a temperature in the range of 40 °C-70 °C to get (lS)-(2-hydroxy-l-phenyl-ethyl)-carbamic acid tert-butyl ester.
In above process the polar solvent is selected from ethyl acetate, methyl acetate, dichloromethane, ethylene dichloride and the like.
The base is selected from sodium bi carbonate, potassium bi carbonate, sodium hydroxide, potassium hydroxide and the like.
(ii) (lS)-(2-Hydroxy-l-phenyl-ethyl)-carbamic acid tert-butyl ester is dissolved in polar solvent and water. To this sodium bromide is added. The reaction mixture is cooled to -7 °C to 0 **C and 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO) is added to it. The reaction mixture is stirred for 5 to 25 minutes and at same temperature, a mixture of sodium hypo chlorite solution (pH adjusted between 8.5 to 9.5), sodium bi

carbonate and water is added drop wise to reaction mixture over the period of 30 minutes to 90 minutes at -7 °C to 5 °C and stirred for about 5-20 minutes. Water is added to reaction mass and the organic layer is separated and dried known as reaction mass I.
The polar solvent is selected from dichloromethane, dichloroethane, ethylacetate, tetrahydrofuran, dimethylsulfoxide and the like.
Vinyl magnesium bromide in tetrahydrofuran 1.0 mol. solution is taken in nitrogen atmosphere. To this dichloromethane is slowly added, reaction mixture is cooled to 25 °C. Reaction mass-I in dichloromethane is added drop wise to reaction mixture over a period of 30 minutes. After addition, the reaction mixture is stirred at a temperature in the range of 20-40 °C for a time period in the range of 1 hour to 3 hour. The confirmation of reaction is conformed by TLC. Aqueous ammonium chloride solution is added to the reaction mass at 5-20 "^C. Dichloromethane is added to reaction mass and the separated organic layer is washed with dilute hydrochloric acid solution and sodium bicarbonate solution and brine solution. Organic layer was concentrated to get thick semi solid (lS,2S)-(2-hydroxy-l-phenyl-but-3-enyl)-carbamic acid tert-butyl ester at 45 °C under vacuum.
(iii) (lS,2S)-(2-hydroxy-l-phenyl-but-3-enyl)-carbamic acid tert-butyl ester is dissolved in aromatic solvent. To this dimethoxy propane is added at temperature in the range of 20-40 ^C followed by addition of pyridinium p-toluene sulphonate to reaction mixture. The reaction mixture is heated to 70-95 °C, stirred at same temperature for about 1-5 hours. The reaction mixture is cooled to 30 to 45 °C, and pyridine is added to it to get (4S,5R)-2,2-dimethyl-4-phenyl-5-vinyl-oxazolidine"3-carboxylic acid tert-butyl ester in semi solid form which is further purified using column chromatography using petroleum ether and ethyl acetate as solvent.
The aromatic solvent is selected from toluene, xylene, chlorobenzene, dichlorobenzene, chlorotoluene, benzonitrile, benzotrifluoride and the like.
(iv) (4S,5R)-2,2-Dimethyl-4-phenyl-5-vinyl-oxazohdine-3-carboxylic acid tert-butyl ester is dissolved in polar solvent. To this carbon tetrachloride & water is added followed by addition of base selected from the group consisting of sodium hydroxide, potassium

hydroxide, sodium carbonate and sodium bicarbonate at a temperature in the range of 10-50 °C. The reaction mixture is stirred for 10 to 20 minutes and alkaU metal periodate, such as sodium meta periodate, is added portion wise to the reaction mixture over the period of 20 to 40 minutes. Ruthenium tri chloride is added to reaction mixture at a temperature in the range of 20-40 °C and stirred for about 30 to 40 hours. The reaction mass is filtered and filtrate is washed with ethyl acetate, aqueous layer is cooled to 10-15 °C and acidified with 10% aqueous hydrochloride (2 liters) up to pH-2-3. Aqueous layer is extracted with ethyl acetate. Organic layer is washed with a 2% aqueous Na2S203 and washed with brine solution. Organic layer was concentrated to get thick semi solid at 50 °C in vacuum. Ether is added to get the desired white solid (4S,5R)-5-carboxymethyl-2,2-dimethyl-4-phenyl-oxazoHdine-3-carboxylic acid tert-butyl ester (I).
The polar solvent is selected from acetonitrile, alcohols such as methanol, ethanol, carbon tetrachloride, chloroform, ketonic solvent such as acetone,, MiBK and the like.

The following specific examples are provided to further illustrate this invention and the manner in which it may be carried out.
It will be understood, however, that the specific details given in the examples have been chosen for purposes of illustration and not to be construed as a limitation of the invention. Example 1:
Step (i)
Preparation of (lS)-(2-hydroxy-l-phenyl-ethyl)-carbamic acid tert-butyl ester (II)

Phenyl glycinol (250 grams, 1.82 mol) was dissolved in ethyl acetate (2.25 liters). To this sodium bi carbonate was added at a temperature in the range of 20 ^C to 40 **C and the reaction mixture was stirred for 15 minutes. A solution of Boc anhydride (477 grams, 2.18 mol) in ethyl acetate (250 mL) was added slowly to reaction mass over a period of 30 minutes. After completion of addition, the reaction mixture was stirred at a temperature in the range of 20-40 "*€ for 30 minutes. After completion of reaction, water was added to the reaction mass. The organic layer was separated and concentrated to the minimum level, to this ether (1.5 liters) was added and stirred for 30 minutes, filtered and dried at 50 °C to get (lS)-(2-hydroxy-l-phenyl-ethyl)-carbamic acid tert-butyl ester. Weight: 383 grams Yield: 89-92% Purity: 99.69% Chiral purity: 99-100%

step (ii)
Preparation of (lS,2S)-(2-hydroxy-l-phenyl-but-3-enyl)-carbamic acid tert-butyl ester
(III)

Step ii-a:
(lS)-(2-Hydroxy-l-phenyl-ethyl)-carbamic acid tert-butyl ester (150 grams, 0.632
mol) was dissolved in dichloromethane (DCM) (2.4 liters), and DM water (600 mL), to this sodium bromide (65.1 grams, 0.632 mol) was added. The reaction mixture was cooled to -5 **C and 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO) (0.99 grams, 0.006 mol) was added to it. The reaction mixture was stirred for 15 minutes and at same temperature, a mixture of sodium hypo chlorite solution (pH adjusted to 9) (840 mL), sodium bi carbonate (155 grams) and DM water (1200 mL) was added drop wise to reaction mixture over the period of 1 hour at -5 °C and stirred for about 5-10 minutes. DM water (5 liters) was added to reaction mass and two layers were separated. Organic layer was separated and aqueous layer was extracted with dichloromethane (1x1.5 liters). Combined organic layer was washed with a solution of 5% aqueous KHSO4 having 5 grams of KI (500 mL) followed by water (1 hter), 2% aqueous sodium thiosulfate NaiSaOs (600 mL) and washed with water (1 liter) and brine solution (600 mL). Organic layer was dried on Na2S04 (150 grams) .Organic layer (ii-a) as such was taken for next step. Step ii- b:
Vinyl magnesium bromide in tetrahydrofuran 1.0 mol. solution (4.5 liters) was taken in nitrogen atmosphere. To this dichloromethane (0.9 liter) was added slowly and reaction mixture was cooled to 25 °C. Then above reaction mass (ii-a) in dichloromethane was added drop wise to reaction mixture over a period of 30 minutes followed by stirring the reaction mixture at a temperature in the range of 25-30 °C for about 2 hours. After completion of reaction aqueous ammonium chloride solution was added to the reaction mass at 5-20 °C. Dichloromethane (750 mL) was added to reaction mass and stirred for

15 minutes. The two layers were separated. Organic layer was washed with 10%
hydrochloride (1x2.5 liters) followed by 5% hydrochloride (2X2.5 liters) and DM water
(2.25 liters) saturated sodium bicarbonate (NaHCOa) solution (1.51t) followed by DM
water (2x2.25 liters) and finally with brine solution (1.5 liters). Organic layer was
concentrated to get thick semi solid (lS,2S)-(2-hydroxy-l-phenyl-but-3-enyl)-carbamic
acid tert-butyl ester at 45 °C.
Weight: 168 grams
Yield: 100%
Purity: 74%
Chiral purity: 98-99%
Step (iii)
Preparation of (4S,5R)-2,2-dimethyl-4-phenyl-5-vinyl-oxazolidine-3-carboxyUc acid tert-butyl ester (IV)

(lS,2S)-(2-hydroxy-l-phenyl-but-3-enyl)-carbamic acid tert-butyl ester (160 grams, 0.608 mol) was dissolved in toluene (1600 mol). To this dimethoxy propane (745 mL, 6.08 mol) was added at temperature in the range of 20-40 °C followed by addition of pyridinium p-toluene sulphonate (2.3 grams, 0.00912 mol) to reaction mixture. The reaction mixture was heated to 80-85 °C, and stirred at same temperature for about 2-3 hours. The reaction mixture was cooled to 45 °C, and pyridine (3 mL) was added to it to get semi solid compound (4S,5R)-2,2-dimethyl-4-phenyl-5-vinyl-oxazolidine-3-carboxylic acid tert-butyl ester.
The residue was dissolved in minimum quantity DCM and spread over a layer of silica gel (100-200 mesh). After drying, this impregnated siUca gel is placed over a layer of silica gel (100-200 mesh), filled into a column to a height of 4 ft. The column is run initially with petroleum ether and later with increasing concentrations of ethyl acetate in

petroleum ether varying from 0-3%. The fractions are checked for the required compound. The fraction containing the compound are collected and evaporated to get the required compound as a light yellow syrup, which is further purified using column chromatography using petroleum ether and ethyl acetate and was distilled at 120 °C to 140 °C at 1 to 5 mm vacuum. Weight: 80-85 grams Yield: 45-50% Purity: 70-75% Chiral purity: 97-99%
Step (iv)
Preparation of (4S,5R)-5-carboxymethyl-2,2-dimethyl-4-phenyl-oxazolidine-3-carboxylic acid tert-butyl ester (I)

(4S,5R)-2,2-dimethyl-4-phenyl-5-vinyl-oxazoHdine-3"CarboxyUc acid tert-butyl ester (75 grams, 0.25 mol) was dissolved in acetonitrile (450 mL). To this carbon tetrachloride (450 mL) & DM water (750 mL) was added followed by addition of sodium bi carbonate (135 grams, 1.36 mol) at a temperature in the range of 20-40 °C. The reaction mixture was stirred for 15 minutes and sodium meta periodate (291 grams, 2.18 mol) was added portion wise to the reaction mixture over the period of 30 minutes. Ruthenium tri chloride (8.2 grams, 0.039 mol) was added to reaction mixture at a temperature in the range of 20-40 °C and stirred for about 36 hours. The reaction mass was filtered and filtrate was washed with ethyl acetate (3X750 mL), aqueous layer was cooled to 10-15 °C and acidified with 10% aqueous hydrochloride (2 liters) up to pH-2-3. Aqueous layer was extracted in to ethyl acetate (3X1 liter). Combined organic layer was washed with a 2% aqueous Na2S203 (600 mL) and washed with brine solution (500 mL). Organic layer was concentrated to get thick semi solid at 50 °C in vacuum. To this pet

ether (25 mL) added to get the desired white soUd (4S,5R)-5-carboxymethyl-2,2-
dimethyl-4-phenyl-oxazolidine-3-carboxyUc acid tert-butyl ester (I),
Weight: 55.61 grams
Yield: 70%
Purity: 95-97%
Chiral purity: 98-99%

We Claim:
1. An improved process for preparing a compound of the formula (I)

which comprises:
(i) protecting the amino group of phenyl glycinol by dissolving it in a solvent in presence of base at a temperature in the range of 20-40 °C and treating with a reagent for introducing t-butoxycarbonyl group, to the reaction mixture to obtain the compound of formula (II);
(ii) oxidizing compound of formula (II) in presence of TEMPO, halogenated alkali metal, hypochlorite and base in a aqueous/solvent mixture at low temperature followed by addition of the obtained carbonyl intermediate as a solution in a solvent to vinyl magnesium halide, Grignard solution in a solvent to obtain compound of formula (III);
(iii) protecting the hydroxyl group by dissolving compound of formula (III) in an organic solvent, followed by addition of a protecting reagent at a temperature in the range of 20 "^C to 40 ^C and a catalyst, and further heating the reaction mixture at a temperature in the range of 50-105 °C, for a duration of 1-5 hours to obtain the compound of formula (IV);
(iv) optionally purifying the compound of formula (IV) by column chromatgraphy in presence of polar solvent and eluting such as ether initially and later with increasing concentrations of ethyl acetate in ether.
(v) oxidizing compound of formula (IV) by means of an alkah metal periodate, in the presence of a catalyst and base. The reaction is carried out in aqueous/organic medium at a temperature in the range of 20 **C to 40 °C.
2. The process as claimed in claim 1 wherein column chromatography in step (iv) is performed for getting pure product of formula (I).
3. A process as claimed in claim 1 wherein said solvent in step (i) is selected from

ethyl acetate, methyl acetate, dichloromethane, ethylene dichloride.
A process as claimed in claim 1 wherein said base in step (i) is sodium bi
carbonate, potassium bi carbonate, sodium hydroxide, potassium hydroxide.
A process as claimed in claim 1 wherein step (i) is carried out for the time period
of2to4hrs.
A process as claimed in claim 1 wherein said solvent in step (ii) is selected from
dichloromethane, dichloroethane, ethylacetate, tetrahydrofuran, dimehtyl
sulfoxide.
A process as claimed in claim 1 wherein said halogenated alkali metal in step (ii)
is selected from sodium bromide, potassium bromide.
A process as claimed in claim 1 wherein step (ii) is carried out at temperature in
the range -7 °C to 5 °C.
A process as claimed in claim 1 wherein step (ii) is carried out for time period of
2 to 5 hrs.
A process as claimed in claim 1 wherein said solvent in step (iii) is selected from
toluene, xylene, benzene.
A process as claimed in claim 1 wherein said protecting agent in step (iii) is
dimethoxy propane.
A process as claimed in claim 1 wherein step (iii) is carried out at temperature in
the range of 40 to 100 X.
A process as claimed in claim 1 wherein step (iii) is carried out for time period of
2 to 6 hrs.
A process as claimed in claim 1 wherein said solvent in step (iv) is selected from
acetonitrile, acetone, alcohols such as methanol, ethanol, carbon tetrachloride,
chloroform.
A process as claimed in claim 1 wherein said alkali metal per iodate in step (iv) is
selected from sodium meta periodate.
A process as claimed in claim 1 wherein base in step (iv) is selected from sodium
bi carbonate, potassium bicarbonate.
A process as claimed in claim 1 wherein step (iv) is carried out at temperature in
therangeof20to60°C.

18. A process as claimed in claim 1 wherein step (iv) is carried out for time period of 2 hrs to 40 hrs.