Indian Patents. 253899:AN IMPROVED PROCESS FOR THE PREPARATION OF (E,Z)-2-{2[[(ARALKYLOXY OR ALKYLOXY)CARBONYLAMINO]-4-THIAZOLYL}-PENT-2-ENEDIOIC ACID

Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF (E,Z)-2-{2[[(ARALKYLOXY OR ALKYLOXY)CARBONYLAMINO]-4-THIAZOLYL}-PENT-2-ENEDIOIC ACID
Abstract	The present invention provides an improved process for the preparation of Ceftibuten. More particularly, the present invention relates to an improved process for the preparation of Ceftibuten intermediate of the formula (I). I wherein R is amino protecting group.

Full Text	Field of the Invention The present invention provides an improved process for the preparation of thiazolyl derivative used as an intermediate in the preparation of cephalosporin antibiotic. More particularly, the present invention relates to an improved process for the preparation of Ceftibuten intermediate of the formula (I). I wherein R is amino protecting group. Background of the Invention U.S. Pat. No. 4,634,697 describes cephalosporin compounds including Ceftibuten, a commercially important third generation cephalosporin type antibiotic of formula (VII). The synthesis of Ceftibuten starting from penicillin G is described in Yoshioka, Pure Appl. Chem., 59, 1041 (1987). However, this process is costly and inefficient leaving a current need for a more cost effective and efficient process for the commercial scale preparation of ceftibuten. The electrochemical transformation of derivatives of cephalosporin C is reported in Jones, et al., J. Pharm. Pharmac, 20, (Suppl.) 45S-47S (1968), and Hall, J. Pharm. Sci., 62, (6) 980-983 (1973). The formation of 3-exomethylene cephalosporins via eletrochemical reduction is described in Ochiai, et al., J. Chem. Soc, Perkin Trans. I, 258-262 (1974) and U.S. Pat. Nos. 3,792,995 and 4,042,472. Baldwin, et al., Tetrahedron, 49, (22) 4907-4922 (1993), also describes the electrochemical reduction of cephalosporin C to form a 3-exomethylene compound. The electrochemical processes described above are chemically inefficient, providing low yields. According to the literature evidence, in the process of preparation of Ceftibuten, two key intermediates are widely employed namely 7[3-aminocephem-4-carboxylic acid or its salts or esters and (E,Z)-2-{2-[[(benzyloxy)carbonyl]amino]-4-thiazolyl} -pent-2-enedioic acid. In view of the vital antibiotic activities of Ceftibuten or its derivatives of the formula (VII), various methods of preparation were reported that utilize the compound of formula (I). Many processes are known in the literature for the preparation of compound of formula (I). US 4,652,652 discloses the preparation of compound of formula I. The aforementioned prior art involves drawbacks like more number of steps including protection and deprotection of esters, usage of alkoxyacrylic acid or its derivatives, which are hazardous and environmentally not safe. The processes involve cumbersome workups and lower yields. Considering the foregoing limitations, we undertook an investigation in our lab to develop a process, which involves less number of steps and succeeded with a process, which yield the title compound in good quality, quantity and eco-friendly manner. Objectives of the Invention The main objective of the present invention is to provide an improved process for the preparation of (E,Z)-2-{2[[(aralkyloxy or alkyloxy)carbonyl]amino]-4-thiazolyl}-pent-2-enedioic acid (DIACID) of formula (I). Another objective of the present invention is to provide a commercially viable process for the preparation of DIACID or its derivatives of formula (I), which would be easy to implement on manufacturing scale. Still another objective of the present invention is to obviate usage of toxic and hazardous chemicals like acrylaldehyde, alkoxyacrylicacid or its derivatives. Summary of the Invention Accordingly, the present invention provides an improved process for the preparation of (E,Z)-2-{2[[(aralkyloxy or alkyloxy)carbonyl]amino]-4-thiazolyl}-pent-2-enedioic acid formula (I) Detailed description of the invention The first aspect of the present invention is to provide an improved process for the preparation of (E,Z)-2-{2[(aralkyloxy or alkyloxy)carbonyl]amino]-4-thiazolyl}-pent-2-enedioic acid formula (I). The said process comprising the steps of cyclizing aralkyl or alkyl 4-haloacetoacetate, preferably ethyl 4-chloroacetoacetate with thiourea to give compound of formula (II). The amino group in compound of formula (II) is protected with a suitable protecting group and then converted to compound of formula (IV) in presence of ethyl formate and metal alkoxide. Reacting compound of formula (IV) with alkyl (triphenylphosphoranylidene)acetate of formula (V) to yield compound of formula (V), followed by hydrolysis of ensuing compound of formula (VI) in presence of a base to result Diacid (compound of formula I). In an embodiment of the present invention, the base used in step (i) is selected from metal carbonate like sodium carbonate, metal hydroxide like NaOH, organic amines like TEA, TMG and the like preferably sodium bicarbonate; and organic solvent used in step (i) is selected from acetone, ethyl methyl ketone, acetonitrile, diglyme, monoglyme, dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO), ethyl acetate, THF, dioxane, methanol, water or mixtures thereof; preferably acetone, acetonitrile and water or mixtures thereof. The substituted or unsubstituted alkyl haloformate used in step (ii) is selected from benzyl chloroformate, p-nitrobenzyl chloroformate, p-methoxybenzyl chloroformate, ethyl chloroformate, and di-tertiary-butyldicarbonate (Boc anhydride). In still another embodiment of the present invention, the solvent used in step (ii) is selected from MDC (dichloro methane), ethyl acetate, toluene, IPE, butyl acetate, water, chloroform and the like or mixtures thereof. In yet another embodiment of the present invention, the alkyl formate used in step (iii) is selected from (1 to 3) C alkyl formate preferably, with ethyl formate; base used in step (iii) is selected from alkoxides, hydroxide, carbonate, hydrides or organo lithium compounds or the like of lithium, sodium, potassium preferably potassium tert.butoxide; the organic solvent used in step (iii) is selected from ether, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, N-methylpyrrolidone, tetrahydrofuran, dioxane, or a mixture thereof. In still another embodiment of the present invention, in step (iv) the alkyl or aralkyl (triphenylphosphoranylidene) acetate of formula (V) is prepared by reacting the alkylhaloacetate like ethylbromoacetate with triphenylphosphine by utilizing the technique known in the prior art. In one more embodiment of the present invention, the hydrolysis of compound of formula (VI) is carried out by either an acid such as con. HC1, sulfuric acid or by base such as NaOH, KOH and the like. In yet another embodiment of the present invention the alkyl group represented by the present invention denotes lower alkyl having 1-6 carbon atom either linear or branched, like ethyl, methyl, isopropyl, butyl and the like; and arylalkyl denotes groups like benzyl, diphenyl methyl and the like; and the halo group denotes bromo, chloro, iodo and the like. The compound of formula (I) prepared according to the present invention, is further converted into Ceftibuten or its hydrate, by utilizing the technique known in the art as per the scheme -II or by following the reference example provided in the specification. The compound of formula (B) is prepared by utilizing the technique known in the prior art or by utilizing the technique given in the scheme-Ill. According to scheme (III) the compound of formula (U) is reduced using NaBH4 in acetic acid medium, after completion of the reaction the mass was quenched in water to yield the compound of formula (V), which is converted to compound of formula (W) using p-toluenesulfonyl chloride or methanesulfonyl chloride in MDC or ethyl acetate using base and after completion of reaction, quenched in acidic solution and followed by extraction into an organic solvent, which is distilled to yield a residue and crystallized with methanol and isopropyl ether. The compound of formula (W) is converted to (X) using a base and then deprotected using phenol or phenol/TFA in a solvent medium selected from ethyl acetate, butyl acetate. This is followed by extracting the product in aqueous medium using sodium bicarbonate solution and insitu deacylation using pen-G-amidase and isolating the compound of formula (Z) at low pH by the process known in the art using a solvent system water, methanol, acetone. The compound of formula (Z) is an important intermediate in the preparation of Ceftizoxime or ceftibuten. Accordingly the Ceftizoxime is prepared by utilizing the technique given in our application No. 784/MAS/2002, and converted to sodium using sodium 2-ethyl hexonate in aqueous acetone medium. Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure. The present invention is exemplified by the following example, which is provided for illustration only and should not be construed to limit the scope of the invention. Example 1 Preparation of Ethyl 2-amino-4-thiazoleacetate (II) To a suspension of thiourea (101.8 g) in water (1000 mL) at 0±2°C, ethyl 4-chloroacetoacetate (200 g), acetone (400 mL) and sodium bromide (50 g) were added. To the resulting mixture, sodium bicarbonate was added while maintaining the pH 5.5-6.0 at 0±2°C for 2 hours and stirred at 0-5°C till completion of the reaction. After completion of reaction, the pH of the reaction mixture was adjusted to 2.0 using dilute sulfuric acid and washed with dichloromethane (400 mL). The pH of the reaction mixture was adjusted to 6.0-6.5 using sodium bicarbonate at 0-5°C. The product obtained was stirred for 1 hour at 0-5°C and filtered. The solid was washed with chilled water, and dried under vacuum to give pure title compound (200 g). Example 2 Preparation of Ethyl 2-[2-[[(benzyloxy)carbonyI]amino]-4-thiazolyl] acetate (III) Into a solution of ethyl 2-amino-4-thiazoleacetate (200 g) in dichloromethane (1400 mL) and water (800 mL) at 0-5°C, benzyl chloroformate (50% in toluene, 734 g) was added maintaining the pH 5.5-6.0 using aqueous ammonia for 2 hours. The organic layer was separated and the aqueous layer extracted with dichloromethane. Combined organic layers were washed with chilled water (2 x 2000 mL), & concentrated into a thick mass. Hexane (2000 mL) and methanol (50 mL) were added and the resulting slurry stirred for long hour and then cooled to 0-5°C. The solid obtained was filtered and washed with hexanes. Drying under vacuum afforded pure title compound (335 g). Example 3 Preparation of Ethyl 2-[2-{[(benzyloxy)carbonyl]amino}-4-thiazolyl]-3-oxopropanoate (IV) To a suspension of potassium tert.butoxide (120 g) in tetrahydrofuran (200 mL) at -25 to -20°C, a solution of ethyl 2-[2-[[(benzyloxy)carbonyl]amino]-thiazolyl]acetate (100 g) in tetrahydrofuran (800 mL) was added. The reaction mixture was stirred at -30 to -10°C for 1 hour. Ethyl formate (130 gm) was added into the reaction mixture in 1 hour. After completion of reaction acetic acid was added at -10 to -5°C. Tetrahydrofuran was distilled off under vacuum at 20°C to thick mass, and ethyl acetate (500 mL) and water (500 mL) added. The organic layer was separated and washed with water followed by sodium bicarbonate solution. The organic layer was separated and concentrated to thick mass. Methanol was added and cooled to -25°C. The solid was filtered and washed with chilled methanol. The solid obtained was dried under vacuum to get pure title compound (96 g). Example 4 Preparation of Ethyl (triphenylphosphoranylidene)acetate (V) To a solution of triphenylphosphine (157 g) in toluene (500 mL), ethyl bromoacetate (100 g) was added below 60°C under nitrogen atmosphere. The reaction mixture was stirred at 35-40°C. The solid was filtered and washed with toluene (500 mL). The above wet solid was dissolved in toluene (1000 mL) and water (1000 mL). The pH of the reaction mixture was adjusted to pH of 9.0-9.3 using aqueous ammonia and stirred for 1 hour. The toluene layer was separated and distilled off up to thick mass at 45°C under vacuum and diisopropyl ether added. The resulting slurry was stirred, cooled, filtered and washed with diisopropyl ether. Drying the solid at 40-45 °C under vacuum afforded pure title compound (200 g). Example 5 Preparation of (E,Z)-2-{2-[[(benzyloxy)carbonyl]amino]-4-thiazolyI}-pent-2- enedioic acid (I) Into a slurry of ethyl 2-[2-{[(benzyloxy)carbonyl]amino}-4-thiazolyl]-3-oxopropanoate (100 g) prepared according to example (3) in toluene (500 mL) at 45°C, ethyl (triphenylphosphoranylidene)acetate (170 g) prepared according to example (4) was added. The reaction mixture was stirred at 70-75°C till completion of reaction and solvent distilled off under vacuum to get a thick mass {compound of formula (VI)}. The above residue was dissolved in tetrahydrofuran (400 mL) and cooled to 15°C. A solution of sodium hydroxide (57.5 g) in water (575 mL) was added at 15°C and stirred for 1 hour. After completion of reaction, the reaction mass was washed with toluene. Dichloromethane (500 mL) was added to the aqueous layer and the pH adjusted 6.5 using dilute hydrochloric acid. The aqueous layer was separated and the pH adjusted to 3.0 using hydrochloric acid. The solid obtained was filtered and dried under vacuum to afford pure title compound (92 g). Example 6 Preparation of Ethyl 2-amino-4-thiazoleacetate (III) To a suspension of thiourea (101.8 g) in water (1000 mL) at 20 ± 2 °C, ethyl 4-chloroacetoacetate (200 g) and acetonitrile (400 mL) were added. To the resulting mixture, sodium bicarbonate was added while maintaining the pH 5.5 -6.0 at 20 ± 2°C for 4 to 6 hours. The pH of the reaction mixture was adjusted to 2.0 using dilute sulfuric acid at 0 - 5 °C and washed with dichloromethane (400 mL). The aqueous layer was taken as such for next step. Example 7 Preparation of Ethyl 2-[2-[[(benzyloxy)carbonyl]amino]-4-thiazolyl] acetate (IV) To the aqueous layer containing Ethyl 2-amino-4-thiazoleacetate prepared according to example (6) was added dichloromethane (1400 mL) at 0 to 5 °C and pH of the solution was adjusted between 5.5 - 6.0 using aqueous ammonia followed by benzyl chloroformate (50% in toluene, 672 g) was added slowly at a pH in the range 5.5 - 6.0. The organic layer was separated and the aqueous layer extracted with dichloromethane (600 mL). Combined organic layers were washed with chilled water. To the organic layer was added methanol (200 ml) and refluxed for 1 - 2 hours and concentrated to thick mass. To the residue was added n-hexane and stirred for 2 hours 0-5°C. The solid was filtered and washed with n-hexane. Drying under vacuum afforded pure title compound (340 g). Reference Example 1 Preparation of (E,Z)-2 {2 [ [(benzyloxy)carbonyl] amino] -4-thiazolyl} -4- (benzyloxycarbonyl)-2-butenoic acid (A) R1 = benzyl In to a suspension of (E,Z)-2- {2-[[(benzyloxy)carbonyl]amino]-4-thiazolyl}-pent-2-enedioic acid (50 g) and benzyl alcohol (74.57 g) in dichloromethane (400 mL) at 0-5°C was added thionyl chloride (15.1 mL) in dichloromethane (100 mL). The reaction mixture was stirred for 4 h at 10-15°C. To the reaction mixture ethyl acetate (500 mL) and water (200 mL) were added at 0-5°C. The organic layer was neutralized with sodium bicarbonate solution and washed with sodium chloride solution. Concentration of organic layer followed by crystallization in methanol (50 mL) afforded pure title compound (48.5 g). 20°C for 10-12 hours and then filtered. The solid was washed with water (90 mL) and acetonitrile (135 mL) to yield the title compound (24 g). Reference Example 4 Preparation of (E, Z)-3-Methyl-2-butenyl 4-(2'-benzyloxycarboxamido-4'- thiazolyl)-4-carboxy-3-butenoate (A) R1 = prenyl To the suspension of (E5Z)-2-{2-[[(benzyloxy)carbonyl]amino]-4-thiazolyl}-pent-2-enedioic acid (100 g) and prenyl alcohol (118.95 g) in dichloromethane (775 mL) at 0 - 5°C was added methane sulphonic acid (34.5 lg) in dichloromethane (50 mL). The reaction mixture was stirred for 70 hours at 0-5 °C. The reaction mixture was washed with DM water (500 ml). To the organic layer was added DM water (500 ml) and distilled off dichloromethane. To the resulting mixture isopropyl alcohol (300 ml) was added and the pH was adjusted to 5.5 - 6.0 using aqueous ammonia. The resulting slurry was stirred at 25 - 30 °C for 12 hours and cooled to 0-5 °C. The solid was filtered and washed with chilled IPA (200 ml) followed by methanol (100 ml). Drying the solid under vacuum afforded pure title compound. (80 g). We claim, 1) An improved process for the preparation of (E,Z)-2-{2[[(aralkyloxy or alkyloxy)carbonylamino]-4-thiazolyl}-pent-2-enedioic acid of formula (I), I wherein R is amino protecting group, which comprises the steps of: 1) cyclizing alkyl 4-haloacetoacetate with thio urea in the presence of a base and an organic solvent or aqueous organic solvent, at a temperature in the range of 0-50 C to give compound of formula II, wherein Alk is C (1-5) alkyl or aralkyl, 2) protecting amino group of the compound of formula (II) with substituted or unsubstituted, aralkyl or alkyl halo formate in a solvent to produce compound of formula (III), III 3) condensing compound of formula (III) with alkyl formate in presence of a base and an organic solvent to produce the compound of the formula (IV), (iv) reacting compound of formula (IV) with alkyl or aralkyl (triphenyl phosphoranylidene) acetate of formula (V) in an organic solvent at 70-80°C to (v) hydrolyzing the compound of formula (VI) to yield compound of formula I. 2. The process according to Claim 1, wherein the base used in step (i) is selected from sodium carbonate, sodium bicarbonate, triethylamine, sodium hydroxide; organic solvents employed in step (i) is selected from acetone, ethyl methyl ketone, acetonitrile, diglyme, monoglyme, dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO), ethyl acetate, THF, dioxane, methanol, water or mixtures thereof. 3. The process according to Claim 1, wherein the solvent employed in step (ii) is selected from the group tetrahydrofuran, chloroform, dichloromethane (MDC), dichloroethane, ethylacetate, DMSO, butyl aceate acetone and the like or mixtures thereof. 4. The process according to Claim 1, wherein the substituted or unsubstituted, aralkyl or alkyl haloformate used in step (ii) is selected from the group consisting of benzyl chloroformate, p-nitrobenzyl chloroformate, p-methoxybenzyl chloroformate, ethyl chloroformate, and di-tertiary-butyldicarbonate(Boc anhydride). 5. The process according to Claim 1, wherein the alkyl formate employed in step (iii) is ethyl formate; and base used in step (iii) selected from sodium tert- butoxide, sodium hydroxide or sodium carbonate. 6. The process according to Claim 1, wherein the organic solvent used in step (iii) is selected from ether, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, N-methylpyrrolidone, tetrahydrofuran, dioxane, or a mixture thereof. 7. The process according to Claim 1, alkyl or aralkyl (triphenyl phosphoranylidene) acetate of formula (V) used in step (iv) is Ethyl (triphenylphosphoranylidene)acetate. 8. The process according to Claim 1, wherein the hydrolysis in step (v) is done in basic condition using sodium hydroxide. 9. A process as claimed in claim 1, further comprising converting compound of formula (I) into ceftibuten or its hydrate by utilizing conventional technique.

Full Text

Field of the Invention
The present invention provides an improved process for the preparation of thiazolyl derivative used as an intermediate in the preparation of cephalosporin antibiotic. More particularly, the present invention relates to an improved process for the preparation of Ceftibuten intermediate of the formula (I).

I wherein R is amino protecting group.
Background of the Invention
U.S. Pat. No. 4,634,697 describes cephalosporin compounds including Ceftibuten, a commercially important third generation cephalosporin type antibiotic of formula (VII).
The synthesis of Ceftibuten starting from penicillin G is described in Yoshioka, Pure Appl. Chem., 59, 1041 (1987). However, this process is costly and inefficient leaving a current need for a more cost effective and efficient process for the commercial scale preparation of ceftibuten.
The electrochemical transformation of derivatives of cephalosporin C is reported in Jones, et al., J. Pharm. Pharmac, 20, (Suppl.) 45S-47S (1968), and

Hall, J. Pharm. Sci., 62, (6) 980-983 (1973). The formation of 3-exomethylene cephalosporins via eletrochemical reduction is described in Ochiai, et al., J. Chem. Soc, Perkin Trans. I, 258-262 (1974) and U.S. Pat. Nos. 3,792,995 and 4,042,472. Baldwin, et al., Tetrahedron, 49, (22) 4907-4922 (1993), also describes the electrochemical reduction of cephalosporin C to form a 3-exomethylene compound. The electrochemical processes described above are chemically inefficient, providing low yields.
According to the literature evidence, in the process of preparation of Ceftibuten, two key intermediates are widely employed namely 7[3-aminocephem-4-carboxylic acid or its salts or esters and (E,Z)-2-{2-[[(benzyloxy)carbonyl]amino]-4-thiazolyl} -pent-2-enedioic acid.
In view of the vital antibiotic activities of Ceftibuten or its derivatives of the formula (VII), various methods of preparation were reported that utilize the compound of formula (I).
Many processes are known in the literature for the preparation of compound of formula (I). US 4,652,652 discloses the preparation of compound of formula I.

The aforementioned prior art involves drawbacks like more number of steps including protection and deprotection of esters, usage of alkoxyacrylic acid or its derivatives, which are hazardous and environmentally not safe. The processes involve cumbersome workups and lower yields.
Considering the foregoing limitations, we undertook an investigation in our lab to develop a process, which involves less number of steps and succeeded with a process, which yield the title compound in good quality, quantity and eco-friendly manner.
Objectives of the Invention
The main objective of the present invention is to provide an improved process for the preparation of (E,Z)-2-{2[[(aralkyloxy or alkyloxy)carbonyl]amino]-4-thiazolyl}-pent-2-enedioic acid (DIACID) of formula
(I).
Another objective of the present invention is to provide a commercially viable process for the preparation of DIACID or its derivatives of formula (I), which would be easy to implement on manufacturing scale.
Still another objective of the present invention is to obviate usage of toxic and hazardous chemicals like acrylaldehyde, alkoxyacrylicacid or its derivatives.
Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of (E,Z)-2-{2[[(aralkyloxy or alkyloxy)carbonyl]amino]-4-thiazolyl}-pent-2-enedioic acid formula (I)

Detailed description of the invention
The first aspect of the present invention is to provide an improved process for the preparation of (E,Z)-2-{2[(aralkyloxy or alkyloxy)carbonyl]amino]-4-thiazolyl}-pent-2-enedioic acid formula (I). The said process comprising the steps of cyclizing aralkyl or alkyl 4-haloacetoacetate, preferably ethyl 4-chloroacetoacetate with thiourea to give compound of formula (II). The amino group in compound of formula (II) is protected with a suitable protecting group and then converted to compound of formula (IV) in presence of ethyl formate and metal alkoxide. Reacting compound of formula (IV) with alkyl (triphenylphosphoranylidene)acetate of formula (V) to yield compound of formula (V), followed by hydrolysis of ensuing compound of formula (VI) in presence of a base to result Diacid (compound of formula I).
In an embodiment of the present invention, the base used in step (i) is selected from metal carbonate like sodium carbonate, metal hydroxide like NaOH, organic amines like TEA, TMG and the like preferably sodium bicarbonate; and organic solvent used in step (i) is selected from acetone, ethyl methyl ketone, acetonitrile, diglyme, monoglyme, dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO), ethyl acetate, THF, dioxane, methanol, water or mixtures thereof; preferably acetone, acetonitrile and water or mixtures thereof.
The substituted or unsubstituted alkyl haloformate used in step (ii) is selected from benzyl chloroformate, p-nitrobenzyl chloroformate, p-methoxybenzyl chloroformate, ethyl chloroformate, and di-tertiary-butyldicarbonate (Boc anhydride).

In still another embodiment of the present invention, the solvent used in step (ii) is selected from MDC (dichloro methane), ethyl acetate, toluene, IPE, butyl acetate, water, chloroform and the like or mixtures thereof.
In yet another embodiment of the present invention, the alkyl formate used in step (iii) is selected from (1 to 3) C alkyl formate preferably, with ethyl formate; base used in step (iii) is selected from alkoxides, hydroxide, carbonate, hydrides or organo lithium compounds or the like of lithium, sodium, potassium preferably potassium tert.butoxide; the organic solvent used in step (iii) is selected from ether, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, N-methylpyrrolidone, tetrahydrofuran, dioxane, or a mixture thereof.
In still another embodiment of the present invention, in step (iv) the alkyl or aralkyl (triphenylphosphoranylidene) acetate of formula (V) is prepared by reacting the alkylhaloacetate like ethylbromoacetate with triphenylphosphine by utilizing the technique known in the prior art.
In one more embodiment of the present invention, the hydrolysis of compound of formula (VI) is carried out by either an acid such as con. HC1, sulfuric acid or by base such as NaOH, KOH and the like.
In yet another embodiment of the present invention the alkyl group represented by the present invention denotes lower alkyl having 1-6 carbon atom either linear or branched, like ethyl, methyl, isopropyl, butyl and the like; and arylalkyl denotes groups like benzyl, diphenyl methyl and the like; and the halo group denotes bromo, chloro, iodo and the like.
The compound of formula (I) prepared according to the present invention, is further converted into Ceftibuten or its hydrate, by utilizing the technique

known in the art as per the scheme -II or by following the reference example provided in the specification.

The compound of formula (B) is prepared by utilizing the technique known in the prior art or by utilizing the technique given in the scheme-Ill. According to scheme (III) the compound of formula (U) is reduced using NaBH4 in acetic acid medium, after completion of the reaction the mass was quenched in water to yield the compound of formula (V), which is converted to compound of formula (W) using p-toluenesulfonyl chloride or methanesulfonyl chloride in MDC or ethyl acetate using base and after completion of reaction, quenched in acidic solution and followed by extraction into an organic solvent, which is distilled to yield a residue and crystallized with methanol and isopropyl ether. The compound of formula (W) is converted to (X) using a base and then deprotected using phenol or phenol/TFA in a solvent medium selected from ethyl acetate, butyl acetate. This is followed by extracting the product in aqueous medium using sodium bicarbonate solution and insitu deacylation using pen-G-amidase and isolating the

compound of formula (Z) at low pH by the process known in the art using a solvent system water, methanol, acetone. The compound of formula (Z) is an important intermediate in the preparation of Ceftizoxime or ceftibuten. Accordingly the Ceftizoxime is prepared by utilizing the technique given in our application No. 784/MAS/2002, and converted to sodium using sodium 2-ethyl hexonate in aqueous acetone medium.

Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure.

The present invention is exemplified by the following example, which is provided for illustration only and should not be construed to limit the scope of the invention.
Example 1
Preparation of Ethyl 2-amino-4-thiazoleacetate (II)
To a suspension of thiourea (101.8 g) in water (1000 mL) at 0±2°C, ethyl 4-chloroacetoacetate (200 g), acetone (400 mL) and sodium bromide (50 g) were added. To the resulting mixture, sodium bicarbonate was added while maintaining the pH 5.5-6.0 at 0±2°C for 2 hours and stirred at 0-5°C till completion of the reaction. After completion of reaction, the pH of the reaction mixture was adjusted to 2.0 using dilute sulfuric acid and washed with dichloromethane (400 mL). The pH of the reaction mixture was adjusted to 6.0-6.5 using sodium bicarbonate at 0-5°C. The product obtained was stirred for 1 hour at 0-5°C and filtered. The solid was washed with chilled water, and dried under vacuum to give pure title compound (200 g).
Example 2
Preparation of Ethyl 2-[2-[[(benzyloxy)carbonyI]amino]-4-thiazolyl] acetate
(III)
Into a solution of ethyl 2-amino-4-thiazoleacetate (200 g) in dichloromethane (1400 mL) and water (800 mL) at 0-5°C, benzyl chloroformate (50% in toluene, 734 g) was added maintaining the pH 5.5-6.0 using aqueous ammonia for 2 hours. The organic layer was separated and the aqueous layer extracted with dichloromethane. Combined organic layers were washed with chilled water (2 x 2000 mL), & concentrated into a thick mass. Hexane (2000 mL) and methanol (50 mL) were added and the resulting slurry stirred for long

hour and then cooled to 0-5°C. The solid obtained was filtered and washed with hexanes. Drying under vacuum afforded pure title compound (335 g).
Example 3
Preparation of Ethyl 2-[2-{[(benzyloxy)carbonyl]amino}-4-thiazolyl]-3-oxopropanoate (IV)
To a suspension of potassium tert.butoxide (120 g) in tetrahydrofuran (200 mL) at -25 to -20°C, a solution of ethyl 2-[2-[[(benzyloxy)carbonyl]amino]-thiazolyl]acetate (100 g) in tetrahydrofuran (800 mL) was added. The reaction mixture was stirred at -30 to -10°C for 1 hour. Ethyl formate (130 gm) was added into the reaction mixture in 1 hour. After completion of reaction acetic acid was added at -10 to -5°C. Tetrahydrofuran was distilled off under vacuum at 20°C to thick mass, and ethyl acetate (500 mL) and water (500 mL) added. The organic layer was separated and washed with water followed by sodium bicarbonate solution. The organic layer was separated and concentrated to thick mass. Methanol was added and cooled to -25°C. The solid was filtered and washed with chilled methanol. The solid obtained was dried under vacuum to get pure title compound (96 g).
Example 4
Preparation of Ethyl (triphenylphosphoranylidene)acetate (V)
To a solution of triphenylphosphine (157 g) in toluene (500 mL), ethyl bromoacetate (100 g) was added below 60°C under nitrogen atmosphere. The reaction mixture was stirred at 35-40°C. The solid was filtered and washed with toluene (500 mL). The above wet solid was dissolved in toluene (1000 mL) and water (1000 mL). The pH of the reaction mixture was adjusted to pH of 9.0-9.3 using aqueous ammonia and stirred for 1 hour. The toluene layer was separated and distilled off up to thick mass at 45°C under vacuum and diisopropyl ether

added. The resulting slurry was stirred, cooled, filtered and washed with diisopropyl ether. Drying the solid at 40-45 °C under vacuum afforded pure title compound (200 g).
Example 5
Preparation of (E,Z)-2-{2-[[(benzyloxy)carbonyl]amino]-4-thiazolyI}-pent-2-
enedioic acid (I)
Into a slurry of ethyl 2-[2-{[(benzyloxy)carbonyl]amino}-4-thiazolyl]-3-oxopropanoate (100 g) prepared according to example (3) in toluene (500 mL) at 45°C, ethyl (triphenylphosphoranylidene)acetate (170 g) prepared according to example (4) was added. The reaction mixture was stirred at 70-75°C till completion of reaction and solvent distilled off under vacuum to get a thick mass {compound of formula (VI)}.
The above residue was dissolved in tetrahydrofuran (400 mL) and cooled to 15°C. A solution of sodium hydroxide (57.5 g) in water (575 mL) was added at 15°C and stirred for 1 hour. After completion of reaction, the reaction mass was washed with toluene. Dichloromethane (500 mL) was added to the aqueous layer and the pH adjusted 6.5 using dilute hydrochloric acid. The aqueous layer was separated and the pH adjusted to 3.0 using hydrochloric acid. The solid obtained was filtered and dried under vacuum to afford pure title compound (92 g). Example 6 Preparation of Ethyl 2-amino-4-thiazoleacetate (III)
To a suspension of thiourea (101.8 g) in water (1000 mL) at 20 ± 2 °C, ethyl 4-chloroacetoacetate (200 g) and acetonitrile (400 mL) were added. To the resulting mixture, sodium bicarbonate was added while maintaining the pH 5.5 -6.0 at 20 ± 2°C for 4 to 6 hours. The pH of the reaction mixture was adjusted to
2.0 using dilute sulfuric acid at 0 - 5 °C and washed with dichloromethane (400 mL). The aqueous layer was taken as such for next step.

Example 7
Preparation of Ethyl 2-[2-[[(benzyloxy)carbonyl]amino]-4-thiazolyl] acetate
(IV)
To the aqueous layer containing Ethyl 2-amino-4-thiazoleacetate prepared according to example (6) was added dichloromethane (1400 mL) at 0 to 5 °C and pH of the solution was adjusted between 5.5 - 6.0 using aqueous ammonia followed by benzyl chloroformate (50% in toluene, 672 g) was added slowly at a pH in the range 5.5 - 6.0. The organic layer was separated and the aqueous layer extracted with dichloromethane (600 mL). Combined organic layers were washed with chilled water. To the organic layer was added methanol (200 ml) and refluxed for 1 - 2 hours and concentrated to thick mass. To the residue was added n-hexane and stirred for 2 hours 0-5°C. The solid was filtered and washed with n-hexane. Drying under vacuum afforded pure title compound (340 g).
Reference Example 1
Preparation of (E,Z)-2 {2 [ [(benzyloxy)carbonyl] amino] -4-thiazolyl} -4-
(benzyloxycarbonyl)-2-butenoic acid (A) R1 = benzyl
In to a suspension of (E,Z)-2- {2-[[(benzyloxy)carbonyl]amino]-4-thiazolyl}-pent-2-enedioic acid (50 g) and benzyl alcohol (74.57 g) in dichloromethane (400 mL) at 0-5°C was added thionyl chloride (15.1 mL) in dichloromethane (100 mL). The reaction mixture was stirred for 4 h at 10-15°C. To the reaction mixture ethyl acetate (500 mL) and water (200 mL) were added at 0-5°C. The organic layer was neutralized with sodium bicarbonate solution and washed with sodium chloride solution. Concentration of organic layer followed by crystallization in methanol (50 mL) afforded pure title compound (48.5 g).

20°C for 10-12 hours and then filtered. The solid was washed with water (90 mL)
and acetonitrile (135 mL) to yield the title compound (24 g).
Reference Example 4
Preparation of (E, Z)-3-Methyl-2-butenyl 4-(2'-benzyloxycarboxamido-4'-
thiazolyl)-4-carboxy-3-butenoate (A) R1 = prenyl
To the suspension of (E5Z)-2-{2-[[(benzyloxy)carbonyl]amino]-4-thiazolyl}-pent-2-enedioic acid (100 g) and prenyl alcohol (118.95 g) in dichloromethane (775 mL) at 0 - 5°C was added methane sulphonic acid (34.5 lg) in dichloromethane (50 mL). The reaction mixture was stirred for 70 hours at 0-5 °C. The reaction mixture was washed with DM water (500 ml). To the organic layer was added DM water (500 ml) and distilled off dichloromethane. To the resulting mixture isopropyl alcohol (300 ml) was added and the pH was adjusted to 5.5 - 6.0 using aqueous ammonia. The resulting slurry was stirred at 25 - 30 °C for 12 hours and cooled to 0-5 °C. The solid was filtered and washed with chilled IPA (200 ml) followed by methanol (100 ml). Drying the solid under vacuum afforded pure title compound. (80 g).

We claim,
1) An improved process for the preparation of (E,Z)-2-{2[[(aralkyloxy or
alkyloxy)carbonylamino]-4-thiazolyl}-pent-2-enedioic acid of formula (I),

I wherein R is amino protecting group, which comprises the steps of:
1) cyclizing alkyl 4-haloacetoacetate with thio urea in the presence of a base and an organic solvent or aqueous organic solvent, at a temperature in the

range of 0-50 C to give compound of formula II,

wherein Alk is C (1-5) alkyl or aralkyl,
2) protecting amino group of the compound of formula (II) with substituted or unsubstituted, aralkyl or alkyl halo formate in a solvent to produce compound of formula (III),

III
3) condensing compound of formula (III) with alkyl formate in presence of a base and an organic solvent to produce the compound of the formula (IV),

(iv) reacting compound of formula (IV) with alkyl or aralkyl (triphenyl phosphoranylidene) acetate of formula (V) in an organic solvent at 70-80°C to

(v) hydrolyzing the compound of formula (VI) to yield compound of formula I.
2. The process according to Claim 1, wherein the base used in step (i) is selected
from sodium carbonate, sodium bicarbonate, triethylamine, sodium hydroxide;
organic solvents employed in step (i) is selected from acetone, ethyl methyl
ketone, acetonitrile, diglyme, monoglyme, dimethylformamide (DMF),
dimethylacetamide (DMAc), dimethylsulfoxide (DMSO), ethyl acetate, THF,
dioxane, methanol, water or mixtures thereof.
3. The process according to Claim 1, wherein the solvent employed in step (ii) is selected from the group tetrahydrofuran, chloroform, dichloromethane (MDC), dichloroethane, ethylacetate, DMSO, butyl aceate acetone and the like or mixtures thereof.
4. The process according to Claim 1, wherein the substituted or unsubstituted, aralkyl or alkyl haloformate used in step (ii) is selected from the group consisting of benzyl chloroformate, p-nitrobenzyl chloroformate, p-methoxybenzyl chloroformate, ethyl chloroformate, and di-tertiary-butyldicarbonate(Boc anhydride).

5. The process according to Claim 1, wherein the alkyl formate employed in step
(iii) is ethyl formate; and base used in step (iii) selected from sodium tert-
butoxide, sodium hydroxide or sodium carbonate.
6. The process according to Claim 1, wherein the organic solvent used in step
(iii) is selected from ether, N,N-dimethylformamide, N,N-dimethylacetamide,
dimethyl sulfoxide, acetonitrile, N-methylpyrrolidone, tetrahydrofuran, dioxane,
or a mixture thereof.
7. The process according to Claim 1, alkyl or aralkyl (triphenyl phosphoranylidene) acetate of formula (V) used in step (iv) is Ethyl (triphenylphosphoranylidene)acetate.
8. The process according to Claim 1, wherein the hydrolysis in step (v) is done in basic condition using sodium hydroxide.
9. A process as claimed in claim 1, further comprising converting compound of formula (I) into ceftibuten or its hydrate by utilizing conventional technique.

Documents:

396-CHE-2005 AMENDED PAGES OF SPECIFICATION 27-02-2012.pdf

396-CHE-2005 AMENDED CLAIMS 27-02-2012.pdf

396-CHE-2005 CORRESPONDENCE OTHERS 30-08-2012.pdf

396-CHE-2005 EXAMINATION REPORT REPLY RECEIVED 27-02-2012.pdf

396-CHE-2005 FORM-1 30-08-2012.pdf

396-che-2005-abstract.pdf

396-che-2005-claims.pdf

396-che-2005-correspondnece-others.pdf

396-che-2005-description(complete).pdf

396-che-2005-form 1.pdf

396-che-2005-form 18.pdf

396-che-2005-form 5.pdf

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Patent Number

253899

Indian Patent Application Number

396/CHE/2005

PG Journal Number

36/2012

Publication Date

07-Sep-2012

Grant Date

31-Aug-2012

Date of Filing

08-Apr-2005

Name of Patentee

ORCHID CHEMICALS & PHARMACEUTICALS LTD

Applicant Address

ORCHID TOWERS, 313, VALLUVAR KOTTAM HIGH ROAD, NUNGAMBAKKAM, CHENNAI-600 034, TAMILNADU, INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	UDAYAMPALAYAM PALANISAMY SENTHIL KUMAR	ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600119, TAMILNADU, INDIA
2	KANAGARAJ SURESHKUMAR	ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600119, TAMILNADU, INDIA
3	SINGARAVEL MOHAN	ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600119, TAMILNADU, INDIA
4	PRABHAT KUMAR SAHOO	ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600119, TAMILNADU, INDIA
5	HITESH CHANDRAPRAKASH SHARMA	ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600119, TAMILNADU, INDIA

PCT International Classification Number

A61K 31/545

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA