WO 98/07691 discloses a process for preparation of 4-alkoxycarbonyl-3-hydroxyethyl azetidinone of Formula VI from L-Threonine of Formula II by a series of reactions depicted in scheme 1 below:
(Scheme Removed)

wherein R1 represents a C1-4 alkyl group and R2 is a protective group for p-lactam ring such as aryl or substituted aryl, particularly 4-methoxyphenyl or 2,4-dimethoxybenzyl.
WO 9807690 discloses a processfor preparation of 4-acetoxy azetidinone of Formula X,
from 4-alkoxycarbonyl azetidinone of Formula VII,
(Formula Removed)

wherein R2 is p-methoxyphenyl, and R1 and R' each independently represent C1-4 alkyl group, by a series of reactions involving hydrolysis of the ester group at 4-position to carboxyl group followed by oxidation of the carboxyl group to acetoxy group and finally deprotection of the azetidinone ring nitrogen using ozone.
The processes reported in the prior-art require extensive column chromatographic purification of intermediates and use of large quantities of solvents and reagents. The present inventors therefore had a reasoned belief that there is a need to provide a process for preparation of 4-acetoxy azetidinone of Formula I that is cost effective, easily scalable with reduced time cycle, which can be accomplished without employing column chromatographic purification.
The present inventors have developed a process for preparation of 4-acetoxy azetidinone of Formula I,
Formula I
wherein R2 is hydrogen or suitable amino protecting group and P is suitable hydroxy protecting group, by careful control of reaction conditions and choice of reagents and solvents in greatly reduced amounts, which provides a cost effective process having a significantly shortened time cycle. The process of the present invention does not involve tedious and costly chromatographic purification steps, at the same time is high-yielding and suitable for scale up synthesis. In the intermediate steps the process of the present invention allows recovery of the solvent, which is reusable without purification.
Suitable hydroxy and amino protecting groups include, but not limited to, lowertrialkylsilyl groups, lowerdialkylhalosilyl groups, nitrogen containing silyl groups, lower alkoxymethyl groups, aralkyl groups, acyl groups, lower alkoxycarbonyl groups, alkenyloxycarbonyl groups and aralkyloxycarbonyl groups, aryl or substituted aryl group selected from, but
not limited to 4-methoxyphenyl or 2,4-dimethoxybenzyl. The silyl groups described above
can be introduced using silylating agents can be selected from the group comprising of
trimethylchlorosilane, tert-butyldimethylchlorosilane, 1,1,1,3,3,3,-hexamethyl disilazane,
n-trimethylsilylacetamide, tetramethyldisilazane, bis(trimethylsilyl)acetamide,
vinyltriacetoxysilane, dimethylchlorosilane, bromomethyldimethylchlorosilane,
di(chloromethyl)tetramethyldisilazane, vinyltriethoxysilane and the like.
A first aspect of the present invention provides a process for preparation of 4-acetoxy azetidinone of Formula I,
Formula I
wherein R2 is hydrogen or suitable amino protecting group and P is suitable hydroxy protecting group, said process comprises of
a) stirring a basified reaction mixture comprising L-threonine of Formula II,
(Formula Removed)
an acid and alkali metal nitrite, for less than 10 hours, to obtain (2R,3R)-epoxybutyric acid of Formula III,
Formula III
b) condensing epoxyacid of Formula III obtained in step a) with glycine ester of Formula
IV,
i-ormuia iv wherein R1 is C1-4 alkyl group and R2 is as described above, in the presence of a condensing agent in a halogenated solvent to obtain epoxyamide of Formula V,
(Formula Removed)

Formula V wherein R1 and R2 are as described above
c) converting the epoxyamide of Formula V obtained in step b) to hydroxy azetidinone
ester of Formula Via,
(Formula Removed)

Formula Via
wherein R1, R2 are as described above, by treatment with a base in less than 10 volumes of tetrahydrofuran with respect to epoxyamide of Formula V
d) converting hydroxy azetidinone ester of Formula Via obtained in step c) to azetidinone
ester of Formula Vlb,
rormuiaVID wherein R1, R2 are as described above, and P is hydroxy protecting group, by treatment with a hydroxy protecting agent in the absence of a reaction solvent
The present invention provides a cost effective and industrially advantageous process for the preparation of 4-acetoxy azetidinone of Formula I,
(Formula Removed)

Formula I
wherein R2 is hydrogen or suitable amino protecting group and P is suitable hydroxy protecting group.
Thercompounds of Formula I are important synthetic intermediates of p-lactam antibiotics that possess the carbapenem and penem ring systems such as imipenem, ertapenem, faropenem, doripenem, meropenem and the like. The p-lactam antibiotics are commonly prescribed antimicrobial agents with activity against a wide range of both Gram-positive and Gram-negative bacterial
US 5081239 and US 5204460 disclose a process for preparation of 4-acetoxy azetidinone (hereafter referred to as AAZ) of Formula I by acetoxylation using acetic acid and an oxidizing agent in the presence of Ruthenium compound as catalyst.
US4861877 discloses a process for preparation of AAZ by reaction of corresponding O-silyl protected compound with acetic anhydride in an organic solvent in the presence of base.
Journal of Chemical Society, Chemical Communication, pp. 662 (1991) discloses a process for preparation of AAZ from (3R)-butane-1,3-diol by reaction of corresponding enol-thioether with chlorosulphonyl isocyanate followed by acetoxylation of the azetidinone so formed at 4-position.
e) hydrolyzing azetidinone ester of Formula Vlb obtained in step d) to carboxy azetidinone
of Formula Vila,
wherein P and R2 are as described above
f) oxidizing the carboxy azetidinone of Formula Vila obtained in step e) in the presence of
an oxidizing agent to obtain 4-acetoxy azetidinone of Formula I,

(Formula Removed)
wherein P and R2 are as described above.
A second aspect of the present invention provides a process for preparation of (2R,3R)-epoxybutyric acid of Formula III (disclosed herein before) wherein a basified reaction mixture comprising L-threonine of Formula I (disclosed herein before), an acid and alkali metal nitrite is acidified with an acid at a temperature less than 20°C.
A third aspect of the present invention provides a process for preparation of (2R,3R)-epoxybutyric acid of Formula III (disclosed herein before) wherein a reaction mixture comprising the said compound is extracted using C4-8 ethers; C^ alcohols; C3.8 ketones; halogenated solvents; polar aprotic solvents, hydrocarbons or a mixture thereof, with a proviso that the organic solvent is not an ester.
(2R,3R)-epoxybutyric acid of Formula III can be converted to 4-acetoxy azetidinone of Formula I by the process disclosed in the first aspect of the present invention. The present inventors have found with respect to the process for preparation of (2R,3R)-
epoxybutyric acid of Formula III reported in Example 1 of WO 98/07691 (herein after the '691 PCT application) that comparable yield of (2R,3R)-epoxybutyric acid can be obtained by stirring the reaction mixture for less than 10 hours at 25°C after addition of 40% w/v sodium hydroxide. In addition, considering the temperature sensitivity and stability of the epoxy acid, it is advantageous to maintain the temperature during acidification of the basified reaction mixture comprising L-threonine of Formula II, an acid and alkali metal nitrite, with concentrated hydrochloric acid, below 20°C. Also in the '691 PCT application, excess ethyl acetate (40 times) is used for extraction of reaction mixture and is often contaminated with acetic acid which interferes in the subsequent amide coupling reaction (step 3) and forms undesired side product(s).
The suitable acid is known to a person having ordinary skills in the art and can be selected from the group comprising hydrochloric acid, hydrobromic acid, nitric acid, p-toluene sulphonic acid and the like. Suitable alkali metal nitrite can be selected from the group comprising sodium nitrite, potassium nitrite and the like. Suitable bases can be selected from the group comprising of alkali metal amides, hydrides, hydroxides, metal alkyls, tertiary amines and bicyclic amines. Tertiary amines can be selected from the group comprising of triethylamine, pyridine, 4-N.N-dimethylamino pyridine, N-methylmorpholine and the like. Bicyclic amines can be selected from the group comprising of DBN, DBU and the like. Suitable solvents for extraction comprise of C4.8 ethers; C1-4 alcohols; C3-8 ketones; halogenated solvents; polar aprotic solvents; hydrocarbon solvents with a proviso that the organic solvent for extraction is not an ester. Suitable condensing agents can be selected from DCC, DBU and the like. The halogenated solvents can be selected from the group comprising of dichloromethane, dichloroethane, chloroform, carbon tetrachloride ethylene bromide and the like. Polar aprotic solvents can be selected from the group comprising of tetrahydrofuran, dimethylformamide, dimethylacetamide and the like. Hydrocarbon solvents can be selected from the group comprising of benzene, toluene, xylene and the like. The solvents described above do not cause undesired side reactions and also can be recovered and reused in the present process without purification.
A fourth aspect of the present invention provides a process for preparation of glycine ester of formula IV,
(Formula Removed)
wherein R1 is C1-4 alkyl group and R2 is hydrogen or suitable amino protecting group, said process comprises of reacting a compound of Formula A,
Formula A wherein R2 is as described above, with 2-halo acetic acid ester of Formula B,
(Formula Removed)

Formula B wherein X is a leaving group and R1 is as described above, in the presence of a base at about 80-100°C.
Glycine ester of Formula IV can be converted to 4-acetoxy azetidinone of Formula I by the process disclosed in the first aspect of the present invention. Suitable bases have already been disclosed in the third aspect of the present invention. Suitable leaving groups represented by X in Formula B above can be selected from the group comprising of Chlorine, Bromine, Iodine, mesyl, or tosyl and the like. The present inventors have found w.r.t. the process for preparation of glycine derivative of Formula IV reported in Example 7 of WO 9807691 that a) the reaction failed to initiate at the reported temperature of 50°C leading to consumption of a large amount of ethylchloroacetate. The reaction suddenly gets initiated whereby the high exothermicity leads to a runaway condition and consequently results in low yield of the glycine derivative of Formula IV b) the present process helps recoveries of the solvent which can be reused without
purification. The quantity of solvent used for washing has also been greatly reduced (less than five equivalents).
A fifth aspect of the present invention provides a process for preparation of epoxyamide of Formula V,
Formula V wherein R1 C1-4 alkyl group and R2 is hydrogen or suitable amino protecting group, the said process comprises of condensing (2R,3R)-epoxybutyric acid of Formula III, (disclosed herein before) with glycine ester of Formula IV (disclosed herein before) in the presence of a condensing agent in a halogenated solvent.
Epoxyamide Formula V can be converted to 4-acetoxy azetidinone of Formula I by the process disclosed in the first aspect of the present invention. Epoxybutyric acid of Formula III and glycine ester of Formula IV can be prepared by methods known in the art or according to the processes disclosed in the present invention. Suitable halogenated solvents have already been disclosed in the third aspect of the present invention.
The process for preparation of epoxyamide of Formula V reported in Example 13 and 14 of WO 9807691 and in Tetrahedron vol. 40, p1795 do not disclose the use of dicyclohexylcarbodiimide (herein after DCC) and a halogenated solvent. The present inventors have found that this amide coupling reaction when carried out in the presence of DCC in a halogenated solvent at a convenient temperature of about -20°C to room temperature, proceeds with nearly 100% conversion as determined by Thin Layer Chromatography. The process of the present invention does not require tedious column chromatography for isolation of the final product, provides good yield of the epoxyamide, which can be used as such in the subsequent reaction step and the in-process used halogenated solvent can be recovered and reused without purification.
A sixth aspect of the present invention provides a process for preparation of hydroxy azetidinone ester of Formula V'»
(Formula Removed)

Formula Via wherein R1 is C1-4 alkyl group, R2 is hydrogen or suitable amino protecting group, said process comprises of, treating epoxyamide of Formula V,
(Formula Removed)

Formula V wherein R1 and R2 are as described above, with a base, in less than 10 volumes of tetrahydrofuran with respect to epoxyamide of Formula V.
Hydroxy azetidinone ester of Formula Via can be converted to 4-acetoxy azetidinone of Formula I by the process disclosed in the first aspect of the present invention. Epoxyamide of Formula V can be prepared by methods known in the art or according to the processes described in the present invention. Suitable bases have already been disclosed in the third aspect of the present invention.
The present inventors have found that the above cyclisation of epoxyamide of Formula V when carried out under reduced quantities of THF proceeds with nearly 100% conversion as determined by Thin Layer Chromatography. The process of the present invention does not require tedious column chromatography purification, provides good yield of the hydroxy azetidinone of Formula Via, which can be used as such in the subsequent reaction step.
A seventh aspect of the present invention provides a process for preparation of azetidinone ester of Formula Vlb,
(Formula Removed)

Formula Vlb wherein R1 is C1-4 alkyl, P is hydroxy protecting group and R2 is hydrogen or suitable amino protecting group, said process comprises of, treating hydroxy azetidinone ester of Formula Via,
(Formula Removed)

Formula Via wherein R1 and R2 are as described above, with a hydroxy protecting agent in the absence of a reaction solvent.
Hydroxy azetidinone ester of Formula Via, wherein R1 and R2 are as described above, can be prepared by methods known in the art or according to the process disclosed in the present invention. Hydroxy azetidinone ester of Formula Via described above was treated with a hydroxy protecting agent for example, a silylating agent in the absence of a reaction solvent, to obtain O-silyl protected azetidinone ester which can be converted to 4-acetoxy azetidinone of Formula I, by the process disclosed in the first aspect of the present invention.
The present inventors have surprisingly found that the silyl protection of side chain hydroxy group in azetidinone ester of Formula Via, wherein R1 and R2 are as described above, can be carried out under solventless conditions with good yield and the product can be used as such in the subsequent reaction step. In addition the present inventors have found w.r.t the process for preparation of silyl azetidinone of Formula VII reported in
Example 1 of WO 9807690 that a) under solventless conditions the reaction times are greatly reduced leading to shortened time cycle b) the process of the present invention does not require tedious column chromatography for isolation of the final product and the in-process used reagents and solvent for washing can be recovered and reused without purification, c) significantly reduced amount of the silylating agent can be used with respect to the hydroxy azetidinone ester of Formula Via.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1 Preparation of ethyl N-p-methoxyphenylglycinate
p-Anisidine (100 g) was dissolved in triethylamine (500 ml) at about 50°C under nitrogen atmosphere. The solution was warmed to 90°C and ethylchloroacetate was added slowly over 2-3 hours. The reaction mixture was refluxed for 0.5 hours and cooled to 40°C and washed with water at the same temperature. The organic layer was cooled to 0°C slowly and stirred for 1 hour and filtered to collect the solids. The solids were washed with 2 x 100 ml of 1:1 of methanol: water mixture and dried under vacuum to obtain the title compound in high purity. Yield =135 g
EXAMPLE 2 Preparation of (2R,3R)-epoxybutyric acid
L-Threonine (100 g) was dissolved in 7.5 N HCI (546 ml) at 0-5°C. To this solution 40% w/v aqueous sodium nitrite (240 ml) was added in 5 hours maintaining temperature -2 to +2°C. The reaction mixture was stirred for 0.5 hours at 0°C, warmed to 25°C, vigorously stirred for 2 hours and then recooled to 0°C. A 40% w/v solution of sodium hydroxide (504 ml) was added maintaining the temperature 0-5°C and stirred for 1-2 hours at 25°C. pH of the solution of was adjusted to 1-1.2 with concentrated hydrochloric acid at 0-5°C. The reaction mass was saturated with sodium chloride and extracted with 3 x 500 ml tetrahydrofuran at pH 1-1.2. Tetrahydrofuran was recovered from the combined extracts
under vacuum at less than 15°C. To the residue dichloromethane (700 ml) was added followed by anhydrous sodium sulfate (100 g). The reaction mixture was stirred for 0.5 to 1 hour and filtered to remove the solids. Dichloromethane (100 ml) washings were added to the above filtrate. This combined filtrate was concentrated under vacuum at less than 15°C to obtain the product. Alternatively, the filtrate was concentrated to half its volume and the solution was used as such for the next step. For additional yields, the aqueous mother liquor after THF extracts may be extracted with THF and worked up as above. Yield =74 g
EXAMPLE 3
Preparation of (2R,3R)-N-(ethoxycarbonyl)methyl-N-p-methoxyphenyl-2,3-
epoxybutyric amide
To a stirred solution of (2R,3R)-epoxybutyric acid (50 g) in dichloromethane, was added ethyl N-p-methoxyphenyl glycinate (92.2 g) at 0-5°C. A solution of dicyclohexylcarbodiimide (101 g) in dichloromethane (75 ml) was added to the reaction mass in 1.5 hours at 0-5°C. To this reaction mixture water (75 ml) was added at 0-5°C followed by stirring at 20-25°C for 1 hour. The reaction mass was filtered to remove solids. The solids were washed with dichloromethane (2 x 75 ml) and the washings added to the filtrate. The filtrate was washed with 2 x 150 ml 3N HCI and 1 x 50 ml saturated sodium bicarbonate solution at 15°C. Dichloromethane was recovered under vacuum to obtain the title compound as a thick oil which can be used as such in the next step. Yield =145 g
EXAMPLE 4
Preparation of (3S,4S)-3-[(1 'R)-1 '-hydroxyethyl]-4-ethoxycarbonyl]-1 -p-
methoxyphenyl-2-azetidinone Method 1:
To (2R,3R)-N-(ethoxycarbonyl)methyl-N-p-methoxyphenyl-2,3-epoxybutyric amide (100 g) was added tetrahydrofuran (500 ml) followed by zinc chloride (7 g) at room temperature. The reaction mass was stirred to dissolve the solids and then cooled to -15°C. Lithium hexamethyldisilazane solution in tetrahydrofuran (20%, 385 ml) was added at -15°C. The reaction mass was brought to 0°C and stirred to completion. The reaction
was then quenched in 2:1 mixture of dichloromethane:dilute hydrochloric acid. The reaction mass was filtered over HYFLO® and the layers separated. The organic layer was washed with water and concentrated under reduced pressure to afford the title compound as thick oil, which can be used as such in the next step. Yield = 98 g
Method 2: Part I:
To a stirred solution of Lithium amide (14.23 g) in tetrahydrofuran (230 ml), was added Hexamethyldisilazane (126.7 g) at 25°C. The resulting solution was refluxed for 3 hours and cooled to 25°C and stored under nitrogen atmosphere.
Part II:
To a stirred solution of (2R,3R)-N-(ethoxycarbonyl)methyl-N-p-methoxyphenyl-2,3-epoxybutyric amide (115 g) in tetrahydrofuran (345 ml), was added zinc chloride (8.05 g) at 25°C. The reaction mixture was stirred for 10 minutes at 25°C and cooled to -15°C. The solution prepared in part I was slowly added into the above reaction mixture at -10 to -15°C in 15 minutes. The resultant mass was stirred at 0°C till the reaction was complete and quenched in a mixture of dichloromethane:dilute hydrochloric acid (575 ml + 719 ml) at 0-2°C and then filtered through HYFLO®. The layers were separated and the organic layer was washed with water and concentrated under vacuum to afford the title compound as a brown solid, which was taken as such to the next step. Yield =112.7 g
EXAMPLE 5 Preparation of (3S,4S)-3-{[(1'R)-1'-t-butyldimethylsilyloxy] ethyl}-4-ethoxy carbonyl-1 -p-methoxyphenyl-2-azetidinone
To (3S,4S)-3-[(1 'R)-1 '-hydroxyethyl]-4-ethoxycarbonyl]-1 -p-methoxyphenyl-2-azetidinone (100g), tert-butyldimethylsilylchloride (56.5 g) and imidazole (27.8 g) were added under stirring at 20°C. The initial exothermicity takes the temperature to about 45°C. The reaction mass was slowly warmed to 90°C when the reaction was complete. The reaction
mass was cooled to room temperature and 400 ml of dichloromethane was added. The separated solids (Imidazole Hydrochloride) were filtered and the filtrate was washed with water. Dichloromethane was then recovered from the organic layer by distillation and the product was obtained as thick oil, which can be used as such in the next step. Yield =135 g
EXAMPLE 6 Preparation of (3S,4S)-3-{[(1'R)-1'-t-butyldimethyl silyloxy]ethyl}-4-carboxy-1-p-
methoxyphenyl-2-azetidinone
To (3S,4S)-3-{[(1 'R)-1 '-t-butyldimethylsilyloxy] ethyl}-4-ethoxycarbonyl-1-p-
methoxyphenyl-2-azetidinone (100g), methanol (500ml) was added. To the methanolic solution was added 245 ml of 1N sodium hydroxide and the reaction mixture was stirred at room temperature till the starting material was completely consumed on Thin Layer Chromatography. Methanol was then recovered under reduced pressure at 30°C. The reaction mass was then diluted with water (1 L), washed with ethyl acetate and further diluted with water (1 L). The pH of the solution was adjusted to 3.5 at 0-5°C and the solids obtained were filtered and washed with water. The solids were then dissolved in 250 ml of acetone at 35°C and 250 ml of water was added slowly. The reaction mass was cooled slowly to 20°C and filtered and the solids washed with 1:1 acetone: water. The solids were dried to obtain the product as off-white to light brown powder, which can be used as such in the next step. Yield =64g Purity -95%
REFERENCE EXAMPLE 7
(3R,4R)-4-acetoxy-3-(((1 'R)-1 ,-t-butyldimethylsilyloxyethyl}-l-p-ethoxy phenyl-2-
azetidinone Method 1:
To a mixed solution of dimethylformamide and acetic acid (3/1, 300 ml), (3S,4S)-3-{[(1'R)-1'-t-butyldimethylsilyloxy]ethyl}-4-carboxy-1-p-methoxyphenyl-2-azetidinone (15 g, 39.5 mmol) was added followed by tetravalent lead acetate (24.5 g, 55.3 mmol) and the
reaction mixture was stirred for 2 hours while maintaining the reaction temperature at 60°C. To the reaction mixture, a mixed solution of ethyl acetate and n-hexane (1:1, 800 ml), and brine (500 ml) were added. The reaction mass was stirred for 30 minutes at room temperature and insoluble materials were filtered off. The filtrate containing the organic layer was washed with brine (400 ml), 10% sodium bicarbonate solution (400 ml) and brine (400 ml) sequentially and concentrated under reduced pressure. The residue was purified by a short column chromatography (eluent: ethyl acetate: hexane = 1:6) to obtain pure title compound as brown oil.
Method 2:
(3S,4S)-3-{[(1 'R)-1 '-t-butyldimethylsilyloxy]ethyl}-4-carboxy-1 -p-methoxyphenyl-2-azetidinone) (15 g, 39.5 mmol) was dissolved in glacial acetic acid (100 ml). To this solution, lead tetraoxide (29.4 g, 43 mmol) was added in small portions at the reaction temperature of 60°C. The reaction temperature slowly rose as the reaction was exothermic. The reaction mixture was vigorously stirred for 30 minutes. After completion of reaction, a small amount of ethylene glycol was added and the solvent removed by evaporation under reduced pressure. The reaction mixture was worked-up as the procedure described in (Method A) to obtain the title compound
REFERENCE EXAMPLE 8 (3R,4R)-4-acetoxy-3-{[(1'R)-1'-t-butyldimethylsilyloxylethyl)-2-azetidinone Method 1:
(3R,4R)-4-acetoxy-3-(((1 'R)-1 '-t-butyldimethylsilyloxylethylJ-1 -p-ethoxy phenyl-2-
azetidinone (26 g, 66 mmol) was dissolved in methanol (500 ml). The internal temperature of the reactor was lowered to -20°C and the reaction was performed for 3 hours with slowly incorporating ozone. After the reaction was completed, 10% solution of sodium thiosulphate and thiourea were added sequentially and the resultant mixture was vigorously stirred for 30 minutes at room temperature. The reaction mixture was concentrated to 1/3 of the initial volume of the mixture. The concentrate was chilled to -
10 C to produce white crystalline powder. The powder was filtered, dried and recrystallized from n-hexane to obtain pure title compound as white crystals.
Method 2:
To lithium perchlorate solution (0.1 M; 45 ml) in mixed solvent of acetonitrile and distilled water (10:1), (3R,4R)-4-acetoxy-3-(((1 'R)-1 '-t-butyldimethylsilylofylethyl}-l-p-ethoxy phenyl-2-azetidinone (349 mg, 1 mmol) was added and dissolved. The mixture was poured in a non-dividable electrolysis vessel with connecting an amorphous carbon anode and a cathode plate, and a Ag/Ag+ reference electrode to a Potentiostat (EG & G 273). Under 1.8 V constant voltage, the mixture was electrolysed until all the starting material disappeared. The organic solvent was removed by evaporation under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with 10% aqueous sodium sulfite solution and saturated brine sequentially and evaporated under reduced pressure. The residue was purified by a short column chromatography (eluent: ethyl acetate: hexane = 1:4) to obtain pure title compound as white crystals.
Method 3:
3R,4R)-4-acetoxy-3-(((1 'R)-1 '-t-butyldimethylsilyloxyethylJ-1 -p-ethoxy phenyl-2-
azetidinone (5 g, 12.7 mmol) was dissolved in acetonitrile (100 ml). After chilling the solution to -15°C, a solution of ceric ammonium nitrate (34.8 g, 63.5 mmol) dissolved in water (150 ml) was added dropwise. The resultant mixture was stirred for 30 minutes. After the completion of the reaction, the mixture was extracted from ethyl acetate (300 ml), and the organic layer was washed with water (200 ml), 10% sodium thiosulphate solution, 10% sodium bicarbonate solution and saturated brine, sequentially and then concentrated under reduced pressure. The brown residue obtained was recrystallized from n-hexane to obtain the title compound as white crystalline powder.

WE CLAIM:
1. A process for preparation of 4-acetoxy azetidinone of Formula I,
wherein R2 is hydrogen or suitable amino protecting group and P is suitable hydroxy protecting group, said process comprises of
a) stirring a basified reaction mixture comprising L-threonine of Formula II,
(Formula Removed)

an acid and alkali metal nitrite, for less than 10 hours, to obtain (2R,3R)-epoxybutyric acid of Formula III,
b) condensing epoxyacid of Formula III obtained in step a) with glycine ester of Formula
IV,
wherein R1 is C1-4 alkyl group, R2 is as described above, in the presence of a condensing agent in a halogenated solvent to obtain epoxyamide of Formula V,

wherein R1 and R2 are as described above
c) converting the epoxyamide of Formula V obtained in step b) to hydroxy azetidinone
ester of Formula Via,
Formula Via
wherein R1, R2 are as described above, by treatment with a base in less than 10 volumes of tetrahydrofuran with respect to epoxyamide of Formula V
d) converting hydroxy azetidinone ester of Formula Via obtained in step c) to azetidinone
ester of Formula Vlb,
Formula Vlb
wherein R1, R2 are as described above, and P is hydroxy protecting group, by treatment with a hydroxy protecting agent in the absence of a reaction solvent
e) hydrolyzing azetidinone ester of Formula Vlb obtained in step d) to carboxy azetidinone
of Formula Vila,
wherein R2 is as described above and P is hydroxy protecting group
f) oxidizing the carboxy azetidinone of Formula Vila obtained in step e) in the presence of an oxidizing agent to obtain 4-acetoxy azetidinone of Formula I,
(Formula Removed)

Formula I wherein P and R2 are as described above.
2. The process according to claim 1 step a) wherein the basified reaction mixture is acidified therein with an acid at a temperature less than 20°C.
3. The process according to claim 1 step a) wherein the basified reaction mixture is acidified and thereafter extracted using C4-8 ethers; C1-4 alcohol; C3-8 ketones; halogenated solvents; polar aprotic solvents, hydrocarbons with a proviso that the organic solvent is not an ester.
4. The process according to claim 1 step b) wherein the condensation is carried out in the presence of dicyclohexylcarbodiimide in dichloromethane.
5. The process according to claim 1 step d) wherein hydroxy azetidinone ester of Formula Via is treated with a silylating agent.
6. The process according to claim 5 wherein the silylating agent is selected from the group comprising of trimethylchlorosilane, tert-butyldimethylchlorosilane, 1,1,1,3,3,3,-hexamethyldisilazane, n-trimethylsilylacetamide, tetramethyldisilazane, bis(trimethylsilyl)acetamide, vinyltriacetoxysilane, dimethylchlorosilane, bromomethyldimethylchlorosilane, di(chloromethyl)tetra methyldisilazane, vinyltriethoxysilane and the like.
7. The process for preparation of 4-acetoxy azetidinone of Formula I according to claim 1, wherein the said process does not employ chromatographic purification.
8. A process for preparation of glycine ester of formula IV,
(Formula Removed)

Formula IV wherein R1 is C1-4 alkyl group and R2 is hydrogen or suitable amino protecting group, said process comprises of reacting a compound of Formula A,
wherein R2 is as described above, with2-halo acetic acid ester of Formula B,

Formula B wherein X is a leaving group and R1 is as described above, in the presence of a base at about 80-100°C.
9. A process for preparation of 4-acetoxy azetidinone of Formula I,
(Formula Removed)
wherein R2 is hydrogen or suitable amino protecting group and P is suitable hydroxy
protecting group, said process comprises of
a) stirring a basified reaction mixture comprising L-threonine of Formula II,
(Formula Removed)

Formula II an acid and alkali metal nitrite to obtain (2R,3R)-epoxybutyric acid of Formula III,
Formula III
b) condensing epoxyacid of Formula III obtained in step a) with glycine ester of Formula
IV, (Formula Removed)

wherein R1 is C1-4 alkyl group, R2 is as described above, to obtain epoxyamide of Formula V,
wherein and R2 are as described above
c) converting the epoxyamide of Formula V obtained in step b) to hydroxy azetidinone
ester of Formula Via by treatment with a base,
roimuia(Formula Removed)
wherein R1, R2 and P are as described above
d) converting hydroxy azetidinone ester of Formula Via obtained in step c) to azetidinone
ester of Formula Vlb,
wherein R1, R2 are as described above, and P is hydroxy protecting group, by treatment with a hydroxy protecting agent
e) hydrolyzing hydroxy azetidinone of Formula Vlb obtained in step d) to carboxy
azetidinone of Formula Vila,
wherein P and R2 are as described above
f) oxidizing the carboxy azetidinone of Formula VIla obtained in step e) in the presence of
an oxidizing agent to obtain 4-acetoxvazetidinone of Formula I,
Formula I wherein P and R2 are as described above, wherein the said process does not employ chromatographic purification at any stage.

10. The process according to claims 1, 8 and 9 wherein the base is selected from the group comprising of alkali metal amides, hydrides, hydroxides, metal alkyls, tertiary amines and bicyclic amines.