Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF MEROPENEM

Abstract Abstract The present invention provides an improved process for the preparation of the formula (I). The compound of the formula (I) is generically known as meropenem and is used as antiobiotic agent in the treatment of pneumonia, urinary tract infections, intra-abdominal, gynecological, skin, and soft tissue infections, meningitis, septicemia and febrile neutropenia.
Full Text Field of the Invention
The present invention provides an improved process for the preparation of the formula (I).
The compound of the formula (I) is generically known as meropenem and is used as antiobiotic agent in the treatment of pneumonia, urinary tract infections, intra-abdominal, gynecological, skin, and soft tissue infections, meningitis, septicemia and febrile neutropenia.
Background of the Invention
In view of the importance of the compound of the formula (I), several synthetic procedures to prepare the compound have been reported.
J. Org. Chem., 1997, 62, 2877-2884 reports a process for the preparation compound of the formula (I). Chinese J. Pharm., 2000, 31, 290-292 also reports a process for the preparation of compound of the formula (I). However, these processes involves tedious purification procedures by column chromatography, which cannot be used in industrial scale operations, though the commercially viable.
With our continued research for developing a process for the preparation of compound of formula (I), we have come up with a process which is not only commercially viable, involves simple purification techniques such as crystallizations, with out decreasing the yields of the product.

Objectives of the Invention
The main objective of the present invention is to provide a simple and commercially viable, industrially scalable process for the preparation of compound of the formula (I).
Another objective of the present invention is to provide a simple and commercially viable, industrially scalable process for the preparation of compound of the formula (I), which avoids chromatographic techniques.
Yet another objective of the present invention is invention is to provide a simple and commercially viable, industrially scalable process for the preparation of compound of the formula (I).


to 10 °C, quenching the reaction mixture by citric acid, followed by iso-propyl ether
extraction to produce compound of formula (V),
iii) phosphorylating the compound of formula (V) using a phosphorylating
agent and mixture of trimethylsilyl chloride and sodium trimethyl silyl amide at a
temperature in the range of -50 °C to 10 °C, extracting the product formed by diiso-
propyl ether to produce a vinyl phosphate of the formula (VI),
iv) reacting the vinyl phosphate of the formula (VI) with the mercaptan of the
formula (VII) in the presence of a solvent at a temperature in the range of -20 °C to
0 °C, the product formed is quenched by phosphate buffer, followed by purification
by di-isopropyl ether to produce a compound of formula (VIII),
v) removing the TBDMS group of the compound of formula (VIII) using
ammonium bifluoride in the presence of NMP and dimethyl acetamide as a solvent,
extracted by ethylacetate, quenched by phosphate buffer, followed by crystallization
with ethyl acetate and IPE mixture to produce a compound of formula (IX),
vi) removing the allyl protecting group in the compound of formula (IX) using
palladium acetate, sodium bicarbonate, dimidone and triethylphosphlte in
tetrahydrofuran at a temperature in the range of 30 °C to 40 °C, extracted the
reaction mixture with ethyl acetate, adjusting the pH of aqueous layer to 5 to 5.5
followed by crystallizing the product with sodium chloride to produce the
compound of formula (X) and
vii) deprotecting the compound of formula (X) using palldium carbon in the
presence of tetrahydrofuran and ethyl acetate, at pH 3.0 to 4.0 extracting with ethyl
acetate, the aqueous layer is lyophiiized to produce compound of the formula (I).
The process is shown in Scheme I.


Description of the Invention
In yet another embodiment of the present invention, the solvent used in step (i) is selected from THF, DCM and the like or mixture thereof.

In yet another embodiment of the present invention, the solvent used in step (ii) is selected from THF, DCM and the like or mixture thereof.
In yet another embodiment of the present invention the phosphorylating agent used is selected from diphenyl chlorophosphate.
In yet another embodiment of the present invention, the solvent used in step (iv) is selected from di-isoproyl ether, acetonitrile and the like or mixture thereof
In yet another embodiment of the present invention there is provided a process for the preparation of compound of formula (VII), which comprises the steps of;
i) reacting the compound of formula (XI) with PNB chloroformate in the presence of base and solvent at a temperature in the range of-10 to 30 °C, filtering at pH 4-5, followed by precipitation with water and methanol, to yield compound of formula (XII),
ii) converting the compound of formula (XII) to compound of formula (XIII) using dimethyl amine hydrochloride and methanesulfonyl chloride in the presence of base and solvent at a temperature in the range of -30 to 20 °C, followed by purification using methanol / IPE,
iii) thioacylating the compound of formula (XIII) using alkali thioacetate in the presence of solvent at a temperature in the range of 40 to 100 °C, followed by purification using toluene/IPE to produce compound of formula (XIV) and iv) hydrolyzing the compound of formula (XIV) using acid in the presence of solvent, followed by crystallizaiton using ethyl acetate and hexane to yield pure compound of formula (VII). The reaction is shown in scheme-II below :


In yet another embodiment of the present invention, the solvent used in step (i) selected from DCM, toluene, ethyl acetate and the like, and base selected from sodium hydroxide, potassium hydroxide and the like.
In yet another embodiment of the present invention, the solvent used in step (ii) sleeted from DCM, THF, EDC, methanol, IPE, hexane and the like or mixtures thereof and base such as triethyl amine, diethyl amine, diisopropyl amine and the like.
In yet another embodiment of the present invention, the solvent used in step (iii) sleeted from toluene, DMF, DMAc, xylene, IPE, hexane and the like or mixtures thereof.
In yet another embodiment of the present invention, the acid used in step (iv) sleeted from HCl, sulfiiric acid and the like and solvent such as methanol, ethanol, ethyl acetate, hexane, IPE and the like or mixtures thereof.
The present invention is illustrated with the following examples, which should not be construed to limit the scope of the invention.

Example 1 Step I
3-{(2R)-2-((3S,4R)-3-l(lR)-l-tert-butyldimethylsnyloxyethyl]-2-oxoazetidin-4-yIJpropionyl}-spiro-[2,3-dihydro-4H-l,3-benzoxazine-2,r-cycIohexan|-4-one
To the suspension of Mg turnings (32.14 gm, 1.32 mol) and I2 (3.2 g, 0.0126 mol) in THF (760 ml) at 60°C, under N2 atmosphere a solution of 1,2-dibromoethane (161.4 g, 0.86 mol) was added for 30 min. After refluxing for 30 min the reaction mixture was cooled to -5°C. A solution of [3R(rR),4R]-4-acetoxy-3-[l-(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone (100 g, 0.348 mol) and 3-(2-bromompropionyl)spiro-[2H-l,3-benzoxazine-2,r-cyclohexan]-4-(3H)-one (134.8 g, 0.383 mol) in THF (190 ml) was added at -5°C during 5 min. The resulted suspension was stirred further at -5 to 0°C for 2 h 30 min. and quenched with ammonium chloride solution (10%, 2800 ml) and extracted with MDC (I x 1200ml, 2 X 600 ml). The combined extracts were washed with DM water (500 ml) and evaporated in vacuo. The residue was purified by stirring with hexane (1000 ml) at 30-35°C for I hour and at 0-5°C for 1 hour. The resulting crystals were collected and washed with hexane (300 ml) and dried at 50°C for 8 hours to afford the title compound (140 g, 80%) as colouriess crystals, mp. 156-158°C. (M^+1 501) [aj^o + 39.1(C=1.0,MeOH)
Step II
3-{(2R)-2-I(3S,4R)-l-[AIIyIoxy carbonylmethyIl-3l(lR)-l-tert-butyldiinethyl
silyloxy ethyl] -2-oxoazetidin-4-yl] -pr opiony 1} sp iro [2,3-dihydro-4H-l ,3-
benzoxazine-2,l'-cycIohexan]-4-one
To a solution of 3-{(2R)-2-[(3S,4R)-3-[(lR)-l-tert-butyl dimethyIsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro-[2,3-dihydro-4H-l,3-benzoxazine-2,r-cyclohexan]-4-one obtained in step I (100 g, 0.2 mol) and allyl bromoacetate (43

g,0.239 mol) in THF (750 ml) at -35 to -30°C under Ni atmosphere powdered sodium hydroxide (25 g,0.625 mol) was added in single lot. After stirring at -30°C for 1 hour 15 minutes, the mixture was poured into the mixture containing 5% citric acid (1500 ml) and IPE (1400 ml) and stirred for 15 minutes at 10°C. The aqueous layer was re-extracted with IPE (500 ml) and the combined extracts were washed with saturate brine solution (1000 ml) and evaporated in vacuo to afford the title compound as colourless viscous oil (120 g). (MS m/z 599 (MVI).
Step III : Allyl (4R,5R,6S)-6-[(R)-l-(tert butyl dimethylsilyloxy)ethyl]-3-
diphenoxy-phosphoryIoxy)-4-methyl-7-oxo-l-azabicycloI3.2.0Jhept-2-ene-2-
carboxylate
To a solution of NaN(TMS)2 (15% in THF, 552 ml, 0.45 mol) under N2 atmosphere a solution of 3-{(2R)-2-[(3S,4R)-l-[allyloxy carbonylmethyl]-3[(lR)-l-tert-butyldimethyl silyloxyethyl]-2-oxoazetidin-4-yl]-propionyl}spiro[2,3-dihydro-4H-l,3-ben20xazine-2,l '-cyclohexan]-4-one obtained in step (II) (100 g, 0.167) in THF (500 ml) was added dropwise at ^0 to -35°C over 20 rain. TMSCl (37 g, 0.34 mol) was added at -30°C and the mixture was stirred at the same temperature for 15 minutes. Diphenyl chlorophosphate (61.3 g, 0.228 mol) was then added at -30°C and the mixture was stirred at -15 to -10°C for 3 hour. The reaction mixture was poured into the mixture containing phosphate buffer (pH 7.0, 1160 ml) and IPE (1160 ml) at 10-15°C. The aqueous layer was re-extracted with IPE (2 x 580 mi). The combined extracts were washed with phosphate buffer (pH 7.0, 2 x 580 ml), saturated brine solution (1000 ml) and evaporated in vacuo. The residue was suspended in hexane (1000 ml) and stirred at -15°C for 1 hour. The resulting crystals were collected by filtration and washed with hexane to recover 34 g (95%) of spiro-[2H-1,3-benzoxazine-2,l '-cyclohexane]-4(3H)-one. The filtrate was

evaporated in vacuo to afford the title compound as light yellow coloured viscous oil (90 g, 92%).
Step IV
Preparation of (4R,5S,6S,8R,2'S 4'S)-allyl-3-[4-(l-p-nitrobenzyloxy carbonyl-
2-dimethylaminocarbonylpyrrolidinyl)thio]-4-metbyl-6-(l-tert-butyldimethyl
silyloxy ethyI)-l-azabicycloI3.2.01-hept-2-ene-7-one-2-carboxyIate
To a solution of allyl (4R,5R,6S)-6-[(R)-l-(tert butyl dimethyIsilyloxy)ethyI]-3-diphenoxy-phosphoryloxy)-4-methyl-7-oxo-l-azabicyclo[3,2.0]hept-2-ene-2-carboxylate obtained in step III (100 g, 0.163 mol) and (2S,4S)-2-dimethylaminocarbonyl-4-mercapto-1 -p-nitrobenzyloxycarbonylpyrrolidone) (43.8 g, 0.124 mol) in acetonitrile (850 ml) at -15 to -10°C under Nj atmosphere, N-ethyl diisopropyl amine (0.147 mol) was added over 10 min. and stirred the reaction mixture for 6 hours. To the reaction mixture, ethyl acetate (850 ml) was added followed by phosphate buffer (pH 7.0, 1700 ml) over 30 minutes by maintaining the temperature between 10 to 15°C and stirred further for 30 min at the same temperature. The aqueous layer was re-extracted with ethyl acetate (2 x 425 ml). The combined extracts were washed with saturated brine solution (2 x 425 ml) and evaporated in vacuo. The residue was stirred with IPE (100 ml) at 30°C for 1 hour and at 0-5°C for 1 hour. The resulted mass was collected to afford the tittle compound (107 g, 92%). MSm/z614(M'+l)
StepV
Preparation of (4R,5S,6S,8R,2'S,4'S)alIyl-3-[4-(l-p-nitrobenzyIoxycarbonyI-2-
dimethylamino carbonyIpyrrolidinyl)thio]-4-methyl-6-(l-hydroxyethyl)-l-
azabicloI3.2.0]-hept-2-en-7-one-2-carboxylate

To a solution of (4R,5S,6S,8R,2'S 4'S)-allyl-3-[4-(l-p-nitrobenzyloxy carbonyl-2-dimethylaminocarbonylpyrrolidinyl)thio]-4-methyl-6-( 1 -tert-butyldimethyl silyloxy ethyl)-1 -azabicyclo[3.2.0]-hept-2-ene-7-one-2-carboxylate (100 g, 0.14 mol) obtained in step (IV) above in DMAc (400 ml) and 1-methyl pyrrolidone (150 ml), powdered ammonium hydrogen difluoride (50 g, 0.876 mol) was added and stirred for 42 hours. The reaction mixture was quenched into the mixture containing phosphate buffer (pH 7.0, 1100 ml) and ethyl acetate (1,100 ml) by maintaining the temperature between 10-15°C. The reaction mass was further stirred for 30 minutes and the aqueous layer was re-extracted with ethyl acetate (2 x 550 ml). The combined ethyl acetate layers were washed with saturated brine solution (3 x 500 ml) and evaporated upto the residual volume of 400 ml. IPE (800 ml) was added to the residue and stirred for 1 hour at 25-30°C and 1 hour at -5 to 0°C. The resulted crystals was collected and washed with IPE (100 ml) to afford the tide compound (70 g, 83%). MSm/z603(M'^+l).
Step VI
Preparation of (4R,5S,6S,8R,2'S,4'S)-3-[4-(l-p-nitrobenzyIoxycarbonyl-2-
dimethylamino carbonylpyrroIidinyl)thio]-4-methyl-6-(l-hydroxyethyl)-l-
azabiclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid
To a solution of NaHCOa (14.1 g, 0.166 mol) dimedone (13.62g, 0.097 mol) was
added under N2 atmosphere and stirred for 30 min. To the resulted clear solution
THF (80 ml) and triethyl phosphite (9.6g, 0.058 mol) was added followed by
palladium acetate (1.86 g, 0.0082 mol) and stirred for 10 min. The resulted
suspension was heated to 35°C and a solution of (4R,5S,6S,8R,2'S,4'S)allyl-3-[4-
(l-p-nitrobenzyloxycarbonyl-2-dimethylamino carbon ylpyrrolidinyl)thio]-4-
methyl-6-(l-hydroxyethyl)-l-azabiclo[3.2.0]-hept-2-en-7-one-2-carboxylate

obtained in step V (lOOg, 0.166 mol) was added over 20 min. The reaction mass was further stirred for 2 hour. Ethyl acetate (200 ml) was added to the cooled reaction mass at 5°C followed by DM water (400 ml) over 30 min. by maintaining the temperature below 10°C and further stirred for 15 minutes. The aqueous layer was re-extracted with ethyl acetate (200 ml) and the pH of the aqueous layer was adjusted between 5.0-5.5 and stirred for 1 hour, at 30°C and further 1 hour at 0°C, and the precipitated solid was separated, washed with water (50 ml) followed by THF (100 ml) and dried under vacuum for 6 hours at 30°C to afford the title compound (60 g, 65%) as off white crystals. [ajo" - 21.2 (0.5 in water) MS m/z 563 (M'^+l)
Step VII
Preparation of (4R,5S,6S,8R,2'S,4'S)-3-(4-(2-Dimethylamino carbonyl) pyr rolidinylthio] -4-methyl-6-( 1-hydroxy ethyl)-! -azab icycio (3.2.0] hep t-2-en-7-one-2-carboxylic acid trihydrate (Meropenem trihydrate)
To a solution of (4R,5S,6S,8R,2'S,4'S)-3-[4-(l-p-nitrobenzyloxycarbonyl-2-
dimethylamino carbonylpyn'oUdinyi)thio]-4-methyl-6-(l-hydroxyethyl)-l-
azabiclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid obtained in step VI (100 g, 0.178 mol), ethylacetate (1000 ml) was added followed by THF (1000 ml) and cooled to 0-5°C. The pH of the reaction mass was adjusted to 4.0 with IN HCl, and sodium chloride (350 g) was added over 5 min, further stirred for 15 min. The aqueous layer was re-extracted with the mixture of ethyl acetate (250 ml) and THF (250 ml) at 0-5°C at pH 4.0. To the combined organic layer DM water (1200 ml) was added followed by Pd-c 10% (95 g, moisturized with 50% water) and hydrogenated under the hydrogen pressure of 4.5 kg for 3 hour at 25-30°C. After removal of Pd-C and organic layer, the aqueous layer was re-extracted with ethyl acetate (500 ml) and dried by vacuum to remove the organic solvent. The water solution was lyophilised

to afford the crude product. The crude was crystallised by water-THF (1:3, 2000 ml) to afford, pure meropenem trihydrate (40 g, 51%) as off white crystals. [a]D"-19.8 (C-0.5, H2O) M.C 12.5%.
Example 2
Preparation of (2S,4S)-2-dimethyiaminocarbonyl-4-mercapto-l-p-
nitrobenzyloxycarbonylpyrrolidone
Step (I)
Preparation of (2S,4R)-2-carboxy-4-hydroxy-l-p-nitrobenzyloxycarbonyl
pyrrolidine
To a solution of sodium hydroxide (65 g, 1.625 mol) in DM water (1390 ml) at 0-
5°C trans-4-hydroxy-L-proline (lOOg, 0.762 mol) was added and stirred for 15
minutes at the same temperature. To the resulted clear solution a solution of PNZ-Cl
(200 g, 0.927 mol) in MDC (720 ml) was added over 20 min and stirred further for
3 hour at 0-5°C and added sodium hydroxide solution (4% 200 ml) stirred for 20
minutes. The aqueous layer was re-extracted with MDC (1000 ml). Methanol was
added to the aqueous layer and the product was precipitated with sulphuric acid (50
g) at 0-5°C, further stirred for 1.5 hour at the same temperature. The crystals was
separated, washed with DM water (500 ml) and dried in vacuo for 10 hour at 50°C
to afford the title compound (222 g, 94%) as colourless crystals.
Step an
Preparation of (2S,4R)-2-diinethylainino carbonyl-4-niesyloxy-l-p-nitrobenzyloxycarbonyl pyrrolidine
To a suspension of (2S,4R)-2-carboxy-4-hydroxy-l-p-nitrobenzyloxycarbonyl pyrrolidine obtained in step I (100 g, 0.322 mol) in MDC (1,150 ml) at 0-5°C, TEA (95 g, 0.938 mol) was added over 15 min and stirred for further 15 minutes at same

temperature to get clear solution. The reaction mixture was cooled to -15 to -10°C, a solution of methane sulphonyl chloride (lOOg, 0.873 mol) in MDC (130 ml) was added the over 25 min. The reaction mixture was stirred for 1 hour at the same temperature. Dimethylamine hydrochloride was added followed by a solution of TEA (99 g, 0.98 mol) in MDC (190 ml) over 340 min at -10°C and stirred further for 1 hour. The reaction mixture was quenched with IN HCl (300 ml) and stirred for 10 min at I0-15°C. The organic layer was separated and washed with NaHCOj solution (5%, 300 ml) followed by DM water (2 x 600 ml) and finally evaporated in vacuo. The residue was purified by a mixture of methanol and IPE (600 ml, 1:1). The precipitated mass was further stirred at -5°C for 1 hour, separated washed with a mixture of methanol and IPE (100 ml, 1:1) and dried in vacuo for 5 hour at 50°C to afford the title compound (100 g, 75%) as colourless crystals.
Step gil)
Preparation of (2S,4S)-4-acetyI thio-2-dimethylamino carbonyl-l-(p-
nitrobenzyloxy carbonylpyrrolidine
To a solution of (2S,4R)-2-dimethylamino cafbonyl-4-mesyloxy-l-p-nitrobenzyloxycarbonyl pyrrolidine obtained in Step II (100 g, 0.24 mol) in DMF (450 ml) and toluene (450 ml), potassium thioacetate (46.5 g, 0.4 mol) was added under N2 atmosphere. The resulted suspension was heated to 70-75°C and stirred for 6 hour. The reaction mass was cooled to 30°C and quenched into a mixture containing toluene (900 ml) and water (900 ml) at 10°C. The aqueous layer was diluted with DM water (900 ml) and re-extracted with toluene (900 ml). The combined extracts were washed with DM water (900 ml) and added hyflow (40 gm) and activated carbon (10 g) and stirred further for 30 minutes at 30°C. Filtered, washed with toluene (100 ml) and the filtrate was concentrated in vacuo upto the

residual volume (300 ml) and added IPE (600 ml), stirred at 55-60°C for 30 min. The precipitated crystals were further stirred for I hour at 10-15°C and separated, washed with a mixture of toluene and IPE (90 ml 1:2) and dried in vacuo at 50-eO^C for 8-10 hours to afford the tittle compound (80 g, 84%). [a]D.+ 8.2 (C=2.0, (CH3)2CO)
Step (W)
Preparation of (2S,4S)-2-dimethylaiiiinocarbonyl-4-mercapto-l-p-
nitrobenzyloxycarbonylpyrrolidone
To a solution of methanolic HCl (20% 500 ml) (2S,4S)-4-acetyl thio-2-dimethylamino carbonyl-l-(p-nitrobenzyloxy carbonylpyrrolidine obtained in step III (100 g, 0.253 mol) was added at 25°C and stirred for 24 hours at 25-30°C. To the clear reaction mixture, MDC (1500 ml) was added and stirred for 15-20 min. The aqueous layer after separation was re-extracted with MDC (500 ml) and the combined organic layers were washed with saturated brine solution (2 x 500 ml), stirred with hyflo (40 g) and carbon (10 g) for 30 min. The organic layer was separated and evaporated in vacuo. The residue was purified with a mixture of ethyl acetate and hexane (1,250 ml, 1:4) to afford the title compound (80 g) as off white crystals. [a]D + 9.7(c-1.0CHCl3)
Advantages of the process :
Step f i):
1. The process avoids the purification by column chromatography
2. Single solvent crystallization yields high optical purity.

Step (ii) :
1. The alkylation is carried out in the presence of a commercially viable base
like sodium hydroxide.
2. The solvent from solvent extraction is changed from a more polar solvent to less polar solvent, since the more polar solvent picks-up polar impurities, which effects the quality of the product.
3. Non-industrially viable column chromatography has been avoided.
Step fiii):
1. Purification is removed, so that the solvent consumption in the process is
reduced, thereby decreasing the cost of the overall process.
Step fiv):
1. The use of DMAc with N-methyi pyrrolidone fastens the reaction. The reaction is completed in 42 hours, whereas the prior-art method is completed in 72 at the same temperature. This makes the process industrially more convenient as the time of the production is drastically decreased.
2. The purification is carried out by simple crystallization techniques thus
avoiding the tedious column purification in the industrial scale.
Step fvi):
1. Purification is carried out by water crystallization thus avoiding purification
using resin yields high purity product.
Step fvii):
1. The process avoids the :
• use of 3-(N-morpholino)propane sulfonic acid (MOPS).

• Usage of high quantity of Pd-C and
• purification using resin.
2. Direct crystalHzation of crude with water-THF yield high purity of the product.



ii) alkylating the compound of formula (IV) using allyl bromoacetate in the presence of sodium hydroxide and a solvent at a temperature in the range of -45 "C to 10 °C, quenching the reaction mixture by citric acid, followed by iso-propyl ether extraction to produce compound of formula (V),



v) removing the lert-butyldimethylsilyloxy (TBDMS) group of the compound of formula (VIII) using ammonium bifluoride in the presence of N-methyl pyirolidone (NMP) and dimethylacetamide as a solvent, extracted by ethylacetate, quenched by phosphate buffer, followed by crystalhzation with ethyl acetate and isopropyl ether (IPE) mixture to produce a compound of formula (IX),

vi) removing the allyl protecting group in the compound of formula (IX) using palladium acetate, sodium bicarbonate, dimidone and triethylphosphlte in tetrahydrofiiran at a temperature in the range of 30 °C to 40 °C, extracted the reaction mixture with ethyl acetate, adjusting the pH of aqueous layer to 5 to 5.5 followed by crystallizing the product with sodium chloride to produce the compound of formula (X) and

vii) deprotecting the compound of formula (X) using palldium carbon in the presence of tetrahydrofiiran and ethyl acetate, at pH 3.0 to 4.0 extracting with ethyl acetate, the aqueous layer is lyophilized to produce compound of the formula (I).
2. The process as claimed in claim 1, wherein the solvent used in step (i) is selected from tetrahydrofiiran (THF), dibromoethane, dichloromethane (DCM) or mixture thereof.
3. The process as claimed in claim 1, wherein the solvent used in step (ii) is selected from THF, DCM and the like or mixture thereof.

4. The process as claimed in claim 1, wherein the phosphorylating agent used is diphenyl chlorophosphate.
5. The process as claimed in claim 1, wherein the solvent used in step (iv) is selected from from di-isoproyl ether, acetonitrile or mixture thereof.

Documents:


Patent Number 198820
Indian Patent Application Number 816/MAS/2002
PG Journal Number 27/2006
Publication Date 07-Jul-2006
Grant Date 12-Apr-2006
Date of Filing 07-Nov-2002
Name of Patentee M/S. ORCHID CHEMICALS & PHARMACEUTICALS LTD
Applicant Address ORCHID TOWERS, 313, VALLUVAR KOTTAM HIGH ROAD, NUNGAMBAKKAM, CHENNAI 600 034
Inventors:
# Inventor's Name Inventor's Address
1 PANDURANG BALWANT DESHPANDE F-3, SAND STONE APARTMENT, FIRST AVENUE, INDRIA NAGAR, CHENNAI - 600 020
2 PANCHAPAKESAN GANAPATHY MELGUDI, NADUIKKOTTAI SIVAGANGA 630 204
3 SENTIL KUMAR KRISHNAN 10/T2, NETHAJI NAGAR RAILWAY FEEDER ROAD ANDIPATTI TALUK, THENI 625 512
PCT International Classification Number C07D477/04
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA