"AN IMPROVED PROCESS FOR CEFPODOXIME ACID"

Field of invention-

The present invention relates to an improved process for the preparation of cefpodoxime acid.

BACKGROUND OF THE INVENTION

Chemically, cefpodoxime proxetil is 1-isopropoxycarbonyloxyethyl (6R,7R)-7-[2-(2- aminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-(methoxy methyl)-3-ceohem-4- carboxylate of formula (IV )and is disclosed in U.S Patent No 4,486,425.

Formula-(IV)

Cefpodoxime acid is a precursor of cefpodoxime proxetil. cefpodoxime acid is prepared from 7-Amino cephalosporanic acid in two steps . 7-Amino -3-methoxymethyl-3-cephem-4- carboxylic acid of formula(I) is derivative of 7-Amino cephalosporanic acid (II) and there have been reported many method for the preparation thereof starting from 7- Aminocephalosporanic acid of formula(II).

Chemically,cefbodoxime acid is [(6R-[6a,7P(Z)]-7-[2-(2-aminothiazol-4-yl)-2- metthoxyimino)acetamido]-3-cephem-4-carboxylic acid having formula( III), and is known from U.S.Pat.No. 4,409,215.

Formula (III)

Cefpodoxime acid is prepared by condensation of 7-Amino -3-methoxymethyl-3-cephem- 4-carboxylic acid (i)with Benzothiazo ί-2- ί (Z)-2-methoxyimino-2-(2-atninothiazoie-4-yl) thioacetate (MAEM) in water miscible solvent under basic condition

Cefpodoxime acid is not suitable for oral administration, its ester derivative, 1- (isopropoxycarbonyloxyl)ethyl ester i.e Cefbodoxime proxetil of formula (IV) is used in the treatment.

Prior art of the invention:

7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid of formula(I) is a precursor of cefpodoxime proxetil, and there have been reported many methods for the preparation thereof starting from 7-aminocephalosphoranic acid (7-ACA) of formula (II).

JP Patent No. 82,192,392 and U.S.patent.No. 4,482,710 teaches preparation of 7-Amino 3- methoxy methyl-3-cephem carboxylic acid by the step of protecting the 7-amino group of 7- ACA with a phenylacetyl group; converting the 3-acetoxy group to a methoxy group by the action of methanol-sodium bicarbonate or methanol-calcium chloride; and removing the protection group. However,this method has the problem that yield obtained are very low(approximately less then 20%) and the process requires multi-steps.

JP Patent No . 84,163,387 teaches a method of preparing 7-Amino3-methoxymethyl-3- cephem-4-carboxylic acid by treating 7-Amino cephalosporanic acid with methane sulphonic acid -methanol. However,this method also has the problem of low yield(approximately 30%) , and the product purity is poor(approximately 30 to40%) due to the formation of by-product such as lactone or the degradition material of the β-lactam ring.

Alternatively,EP Patent No. 204,657 describes 7-amino-3-methoxymethyl-3- cephem-4-carboxylic acid may be obtained by reacting 7-ACA in sulfolane with boron trifluoride-methanol,but this method requires the use of gaseous boron trifluoride which is hazardous and difficult to handle.

EP Patent 262,744 discloses a method of preparing 7-amino-3-methoxymethyl-3- cephem-4-carboxylic acid by reacting 7-ACA with methanol in the presence of a halide of antimony or zinc. However,this method is hampered by the problem of low yield (approximately 40%) and is not suitable for mass production due to use of column chromatography for separating final product.

Further, JP Patent No 88,115,887 discloses 7-amino-3-methoxymethyl-3-cephem-4- carboxylic acid has been prepared by treating 7-Amino cephalosporanic acid with boron trifluoride-methanol in presence of halo sulfonic acid or alkylsulfonic acid .

EP. Patent No.343926 teaches a method of preparing 7-amino-3-methoxymethyl-3- cephem-4-carboxylic acid by reacting 7aminocephalosporanic acid with trimethyl borate in sulfolane, in the presence of sulphuric acid and antimony pentachloride. However,this method requires the use of expensive antimony pentachloride as well as 98% trimethyl borate which is difficult to handle.

EP Patent No.485,204 reveals a method for preparing 7-amino-3-methoxymethyl-3- cephem-4-carboxylic acid by treating 7-ACA in a solution containing an alkoxysulfonic acid with a trialkyl borate and an alkylal. However, this method still has to deal with the difficulty of handling 98% trimethyl borate which is difficult to handle and also suffers from the problem of poor process controllability.

The prior art process for the preparation of 7-Amino -3-methoxymethyl-3-cephem-4- carboxylic acid has one or more limitations enumerated below:

Use of hazardous chemicals preventing smooth commercial production.

Use of expensive chemicals.

Low yield of 7-Amino -3-methoxymethyl-3-cephem-4-carboxylic acid leading to reduced yield of cefpodoxime acid and Cefpodoxime Proxetil. In order to overcome the above limitations, Applicant has developed a process for the preparation of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid, which involves a non aqueous workup of the reaction mixture in a protic solvent medium by treating with two different organic bases in a specific sequential order.

5 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid thus obtained, when used as a

starting material for the preparation of Cefbodoxime acid resulted in enhanced yield of ceipodoxime proxetil having required purity.

The surprising results of the present invention is attributed to an enhanced yield of Cefbodoxime acid by implementing non-aqueous work up of the reaction mixture involving

10 pH adjustment in two stages using two different organic bases in a definite sequence in the

process step for the preparation of 7-AMCA.

The following table provides at glance data of the results.

Exam Reaction Aqueous/ Base Yield of Yield of %Assay Yield of %Assay of pie conditition non aqueous sequence wet 7- cefpodoxi of cefpodo Cefpodoxim

AMCA me acid cefpodo xime e proxetil

Work up

xime proxetil

acid

01 MSA,MeO aqueous ammonia 3.0T 0.81 96.0% 0.972 95.4 H

02 MSA,MeO Aqueous TEA 3.2T 0.80 95.2% 0.960 94.7 H

03 MSA,MeO Non aqueous ammonia 2.3T 1.02 92.5% 1.214 91.5 H

04 MSA.MeO Non aqueous TEA 2.5T 0.98 93.55 1.176 93.1 H

05 MSA,MeO Non aqueous Ammonia I .6T 1.02 98.5% 1.244 98.2 H ,ΤΕΑ

06 MSA,MeO aqueous Ammonia 3.2T 0.82 95.5% 1 .000 0 H ,Ί ^' ΕΑ

07 MSA,Me<) Non aqueous ΤΕΑ,Ατη L8T 0.99 96,0% 1 . i 98 95, ! H moiiia

08 MSA,MeO Aqueous ammonia 3.5T 0.88 90.0% 1.056 89.7 Η,ΤΜΒ

MSA,MeO Aqueous TEA 3.8T 0.89 89.0% 1.086 88.2 Η,ΤΜΒ

MSA, Non aqueous ammonia 2.9T 1.03 91.0% 1.231 90.3

MeOH,

TMB

MSA. Non aqueous TEA 3.2T 1.02 90.0% 1.203 89.8

MeOH ,

TMB

MSA,MeO Non aqueous Ammonia J .9T 1.02 95.5% 1 .231 95,4 Η/ΓΜΒ ,ΤΕΑ

MSA,Me(> Aqueous Ammonia 3.4T 0.85 93.5% 1 .003 93 2 Η,Τ Β ,ΤΕΑ

MSA, eO Non aqueous TEA, Am 2.0T 0.98 94.0% 1.1 86 93.6 Η,Τ Β monia

Sulp olane, aqueous ammonia 3.2T 0.99 95.5% 1.188

BF3,MeOH

Sulpholane, Aqueous TEA 3.0T 1.0 97.5% 1.211 97.3 BF3,MeOH

Sulpholane, Non aqueous ammonia 2.5T 1.00 95.1% 1.202 94.5 BF3,MeOH

Sulpholane, Non aqueous TEA 2.8T 1.01 94.2% 1.212 93.6 BF3.MeOH

Sulpholane, Non aqueous Ammonia 2.0T 1 .02 98.3% 98.0 BF3,MeOH /TEA

Sulpholane, Aqueous Ammon a 3. IT 0..87 94.5% 1 044 94.0 BF3,MeOH ,ΊΈΑ

Sulpholane, Non aqueous TEA., LSI 0.99 96.0% 1.1 8 S 3 BF3,MeOH Ammonia

MSA, Non aqueous Ammonia 1.58 1.01 98,2 1.232 98,0 MeOH, , DEA

MSA Non aqueous Ammonia 1 .8 1.02 ^> 2 1 .228 9 ^s ! 2 ,MeOH, , DJPA TMB

Siil liolane, NOJO aqueous Ammonia L9 1 .01 98, 1 1 .216 98.0 BF3 ,MeOH ,TMG

MSA - Methane sulphonic acid

TMB - Trimethyl borate

BF3 - Boron trifluoride

TEA - Triethylamine

DEA - Diethylamine

DIPA - Diisopropylamine

TMG - Tetramethylguanidine

7-AMCA - 7-Amino 3-methoxy 3-cephem cephalosporanic acid

Yield - Number of fold w.r.t 7-Amino cephalosporanic acid

OBJECTS OF THE INVENTION:

An object of the present invention is to provide a process for preparation of 7-AMCA involving non-aqueous work up starting from 7-Amino cephalosporanic acid.

Another object of the present invention is to provide a process for preparation of Cefpodoxime acid with enhanced yield from 7-AMCA.

Yet another object of the present invention is to provide a process for preparation of Cefpodoxime Proxetil from cefpodoxime acid having an enhance yield and required purity. SUMMARY OF THE INVENTION:

The present invention relates to a process for the preparation of 7-AMCA implementing a non-aqueous work up of the reaction mixture involving treating with two different organic bases in two stages, which is further converted to Cefpodoxime acid with an enhanced yield by conventional method. The invention also provides a process for the preparation of Cefpodoxime proxetil with an enhanced yield. DETAILED DESCRIPTION OF THE INVENTION

In accordance, present invention relates to an improved process for the preparation Cefpodoxime acid comprising steps of reacting 7-Amino cephalosporanic acid ( 7ACA) with a mixture of methane sulphonic acid and methanol or Methane sulphonic acid , Methanol , trimethylborate or sulpholane , BF3 , Methanol at a temperature ranging between 5°C-50°C, followed by addition of calculated amount of methanol. The reaction mixture stirred for 1- 2hours around 5-50°C and worked up by first adjusting the to pH to a value of around 0.5 with methanolic solution of first organic base and then filtering the precipitated solid, followed by adjusting the pH of the filtrate to 3.3 to 3.5 using second organic base . The precipitated 7-Amino 3-methoxymethyl 3-cephem carboxylic acid thus obtained is further converted into Cefpodoxime acid having required purity and enhanced yield by adopting conventional method reported in prior art.

Finally Cefpodoxime acid is converted into Cefpodoxime Proxetil with improved yield by any of the conventional method known in the prior art.

An embodiment of the present invention provides a process in which non-aqueous work up is performed for the preparation of 7-AMCA.

Another embodiment of the present invention provides a process for the preparation of Cefpodoxime acid with enhanced yield.

Yet another embodiment of the present invention uses two organic bases in a specific sequential order to obtain 7-AMCA.

Still yet another embodiment of the present invention provides a process for the preparation of Cefpodoxime acid from 7-AMCA having enhanced yield and required purity.

Another embodiment of the present invention where in the first organic base used for adjusting the pH of the reaction mixture is ammonia in methanol. Yet another embodiment of the present invention wherein the second organic base used for adjusting the pH is selected from triethylamine, diethyl amine, di isopropyl amine and tetramethyl guanidine. Still another r embodiment of present invention provides a process for the conversion of cefpodoxime acid in to cefpodoxime proxetil having an enhance yield.

The present invention is illustrated with the following examples. However, it should be understood that the scope of the present I nvention is not limited by the examples in any manner. It will be appreciated by any person skilled in this art that the present investigation includes following examples and further can be modified and altered within the scope of the present invention .

Example (1)

(A) Added 7-Amino cephalosporanic acid (100gm,0.3676 mol) is added to mixture of methane sulphonic acid(500ml) and methanol(155ml) at a temperature ranging between 5°- 10°C. The reaction mixture stirred for l-2hours around 10-12° and quenched the reaction mass by adding it to chilled water (1000ml) . Added aqueous ammonia solution (630ml 20% ammonia in 470ml water) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC. to attain a pH value of around 0.5 folio wed by adjusting the pH of the solution to 3.3 to 3.5. The precipitated 7-Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 300gm).

(B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (300gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z)"2-methoxyimino-2-(2-aminothiazole~4~yl)thioaceiate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water, adjusting the pH to around 5.5 to 6.0 by using dilute sulphuric acid .. Filtering the solid obtained and treating the filtrate with activated charcoal, followed by filtration and adjusting the pH of the filtrate to 2.6to 2.8 by using dilute sulphuric acid to obtain cefpodoxime acid (81gm,Assay 96.0%).

(C) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes. The reaction mixture was stirred for 30 min . The reaction mixture was worked up by adding Hydrochloric acid (2ml) in (20) ml water maintaining the temperature in the range of -15-10°C.Then Reaction mass is transferred in to mixture of ethyl acetate (200 ml), water 400 ml and Sodium thio sulphate (4.0gm) at 10-15°C . stirred the mass for lOmin , separate the layers. Aqueous layer washed with 100 ml Ethyl acetate . Combined both ethyl acetate layer and washed thrice with 150 ml 10% sodium chloride solution at 15°C. Ethyl acetate layer was treated with activated carbon.

Concentrate ethyl acetate layer under vacuum up to 70.0ml at 25°C. Mass is cooled up to 10°C. Added Methane sulphonic acid solution ( 5.0gm in 200 ml Water) to Concentrated Ethyl acetate mass at 10-15°C, Stir red for 10 minutes then added cyclohexane (52 ml), stirred for 5.0minutes. Separate the aqueous layers . Degas aqueous layer under vacuum for 30 minutes at 20-25 °C .

Methanol (80 ml) is added in aqueous mass at 25°C, followed by addition of 400ml water . Adjust the pH of the mass to 3.8-4.2 by using 5% ammonia solution . stir for 60 minutes . filtered the solid and washed with water and then dried at 40-45°C.( Yield 24.00gm, Assay 95.4% )

Example (2) (A)Added 7-Amino cephalosporanic acid (100gm,0.3676 mol) is added to a mixture of methane sulphonic acid(500ml) and methanol(155ml) at a temperature ranging between 5°- 10°C. The reaction mixture stirred for l-2hours around 10-12° and quenched the reaction mass by adding it to chilled water (1000ml) . Added cone triethyl amine (780gm) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to attain a pH value of around 0.5 followed by adjusting the pH of the solution to 3.3 to 3.5. The precipitated 7-Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 320gm).

(B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (320gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazo i-2-yi (/ )·· 2"meihoxyimino~2~(2"aminoihiazole~ ~yl)†hioaceiaie (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).

(80gm,Assay 95.2%). (C) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of -10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.00gm, Assay 94.7% )

Example (3) (A)Added 7-Amino cephalosporanic acid (100gm,0.3676 mol) is added to mixture of methane sulphonic acid(500ml) and methanol(155ml) at a temperature ranging between 5°- 10°C. The reaction mixture stirred for l-2hours around 10-12° and quenched the reaction mass by adding it to chilled methano 1(1000ml). Added methanolic ammonia solution (126 gm in 1000ml) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to achieve pH value of around 0.5, Filtering the precipitated solid, followed by adjusting the pH of the filtrate to 3.3 to 3.5 by treating with methanolic ammonia solution. The precipitated 7-Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 230gm).

(B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (230gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with

Benzothiazol-2-yl (Z)-2-rnethox nmmo-2-(2-ammol¾iazo]e-4-yi)thioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water, and further worked up following the procedure as described in example 1 step (B).(102gm,Assay 92.5%). ( C) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 23.8gm, Assay 91.5% )

Example (4)

(A) Added 7-Amino cephalosporanic acid (100gm,0.3676 mol) is added to mixture of methane sulphonic acid(500ml) and methanol(155ml) at a temperature ranging between 5°- 10°C. The reaction mixture stirred for l-2hours around 10-12° and quenched the reaction mass by adding it to chilled methano 1(1000ml). Added Tri ethyl amine (780gm) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to attain a pH value of around 0.5, followed by adjusting the pH of the solution to 3.3 to 3.5. The precipitated 7- Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 250gm).

(B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (250gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl

(Z)~2~metlioxyimino-2"(2~amiiiotliiazole"4-yl)tliioacetat e (ΜΑΈΜ) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). 98.0gm, Assay 93.55%). (C ) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide

(100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.00gm, Assay 93.1%)

Example (5)

(A) Added 7-Amino cephalosporanic acid (100gm,0.3676 mol) is added to mixture of methane sulphonic acid(500ml) and methanol(155ml) at a temperature ranging between 5°- 10°C. The reaction mixture stirred for l-2hours around 10-12° and quenched the reaction mass by adding it to chilled methano 1(1000ml). Added methanolic ammonia solution (126 gm in 1000ml) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to achieve pH value of around 0.5 , filtering the precipitated solid, followed by adjusting the pH of the filtrate to 3.3 to 3.5 by treating with triethyl amine. The precipitated 7-Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 160gm).

(B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (160gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z)-2-methoxyimino-2-(2-aminoth¼zole-4-yl)th.ioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).

(102gm,Assay 98.5%).

(C) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in

dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.39gm, Assay 98.2% ) Example (6)

(A) Added 7-Amino ce halosporanic acid (100gm,0.3676 mol) is added to a mixture of methane sulphonic acid(500ml) and methanol(155ml) at a temperature ranging between 5°- 10°C. The reaction mixture stirred for l-2hours around 10-12° and quenched the reaction mass by adding it to chilled water(lOOOml). Added aqueous ammonia solution (630 gm 20% ammonia in 430ml water) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to attain a pH value of around 0.5 followed by adjusting pH of the solution to 3.3 to 3.5 by treating with triethyl amine. The precipitated 7-Amino 3- methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 320gm).

(B) 7-Amino 3 -methoxymethyl 3-cephem carboxylic acid (320gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z)-2-methoxyimino-2-(2-aminoth¼zole-4-yl)th.ioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).

(82gm,Assay 95.5%).

( C ) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.39gm, Assay 95.0% )

Example (7)

(A)Added 7-Amino cephalosporanic acid (100gm,0.3676 mol) is added to mixture of methane sulphonic acid(500ml) and methanol(155ml) at a temperature ranging between 5°- 10°C. The reaction mixture stirred for l-2hours around 10-12° and quenched the reaction mass by adding it to chilled methano 1(1000ml). Added triethyl amine (710gm) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC. to attain a pH value of around 0.5 followed by adjusting the pH of the solution to 3.3 to 3.5 by treating with methanolic ammonia solution. The precipitated 7- Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 180gm).

(B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (180gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z)-2-inethoxyimmo-2-(2-arainothia2:ole-4-y].)thioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).

(99gm,Assay 96.0%).

(C ) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.20gm, Assay 95.1%)

Example(8)

(A) 245ml of methane sulphonic acid was mixed with 60.0mlof an azeo tropic mixture composed of 70% Trimethyl borate and 30% methanol and solution was cooled to 10°C. 7- amino cephalosporanic acid (100 gm,0.3676 mole) was slowly added in 30min and dissolve completely. Then additional 63ml of trimethyl borate azeotropic mixture was added slowly in 80-90 minwhile maintaining the temperature at 10-12°C - The reaction mixture stirred for 60-90min and quenched the reaction mass by adding it to chilled water (1000ml) . Added aqueous ammonia solution (305ml 20% ammonia in 695 ml water) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to attain a pH value of around 0.5 folio wed by adjusting pH of the solution to 3.3 to 3.5. The precipitated 7- Amino 3- methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 350gm).

((B) 7- Amino 3-methoxymethyl 3-cephem carboxylic acid (350gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with

Benzochiazo ί-2-yi (Z)-2-meth.oxyimino-2-(2-ainmothia2'.oIe-4-yl)tWoacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (88gm,Assay 90.0%).

( C) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes. The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.00gm, Assay 89.7% )

Example(9)

A) 245ml of methane sulphonic acid was mixed with 60.0mlof an azeotropic mixture composed of 70% Trimethyl borate and 30% methanol and solution was cooled to 10°C. 7- amino cephalosporanic acid (100 gm,0.3676 mole) was slowly added in 30min and dissolve completely. Then additional 63ml of trimethyl borate azeotropic mixture was added slowly in 80-90 minwhile maintaining the temperature at 10-12°C - The reaction mixture stirred for 60-90min and quenched the reaction mass by adding it to chilled water (1000ml) . Added tri ethymine (385gm) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to attain a pH value of around 0.5 followed by adjusting the pH of the solution to 3.3 to 3.5. The precipitated 7-Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 380gm).

(B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (380gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazo i-2-yi (Z)"2-meihoxyimino-2-(2-aminoihiazole~4~yl)†hioaceiate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).

(89gm,Assay 89.0%). (C ) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.40gm, Assay 88.2% )

Example(lO) A) 245ml of methane sulphonic acid was mixed with 60.0mlof an azeotropic mixture composed of 70% Trimethyl borate and 30% methanol and solution was cooled to 10°C. 7- amino cephalosporanic acid (100 gm,0.3676 mole) was slowly added in 30min and dissolve completely. Then additional 63ml of trimethyl borate azeotropic mixture was added slowly in 80-90 meanwhile maintaining the temperature at 10-12°C - The reaction mixture stirred for 60-90min and quenched the reaction mass by adding it to chilled methanol (1000ml) . Added methanolic ammoinia solution (61.8 gm ammonia in 1000ml methanol slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to achieve pH value of around 0.5, followed by adjusting the pH of the solution to 3.3 to 3.5. The precipitated 7- Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 290gm).

(B) 7- Amino 3-methoxymethyl 3-cephem carboxylic acid (290gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z)~2~metlioxyimino-2"(2~amiiiotliiazole"4-yl)tliioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (103gm,Assay 91.0%).

( C) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes. The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 23.90gm, Assay 90.3% )

Example(ll)

A) 245ml of methane sulphonic acid was mixed with 60.0mlof an azeotropic mixture composed of 70% Trimethyl borate and 30% methanol and solution was cooled to 10°C. 7- amino cephalosporanic acid (100 gm,0.3676 mole) was slowly added in 30min and dissolve completely. Then additional 63ml of trimethyl borate azeotropic mixture was added slowly in 80-90 meanwhile maintaining the temperature at 10-12°C - The reaction mixture stirred for 60-90min and quenched the reaction mass by adding it to chilled methanol (1000ml) . Added triethyl amine (385. Ogm) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to attain a pH value of around 0.5 followed by adjusting the pH of the solution to 3.3 to 3.5. The precipitated 7-Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 320gm).

(B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (320gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazoi-2-yi (Z)"2-methoxyimino-2-(2-aminothiazole~4~yl)thioaceiate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).

(102gm,Assay 90.0%). (C ) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 23.50gm, Assay 89.8%)

Example(12)

A) 245ml of methane sulphonic acid was mixed with 60.0mlof an azeotropic mixture composed of 70% Trimethyl borate and 30% methanol and solution was cooled to 10°C. 7- amino cephalosporanic acid (100 gm,0.3676 mole) was slowly added in 30min and dissolve completely. Then additional 63ml of trimethyl borate azeotropic mixture was added slowly in 80-90 meanwhile maintaining the temperature at 10-12°C . The reaction mixture stirred for 60-90min and quenched the reaction mass by adding it to chilled methanol (1000ml) . Added methanolic ammonia solution (126 gm in 1000ml) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to achieve pH value of around 0.5,Filtering the precipitated solid, followed by adjusting the pH of the filtrate to 3.3 to 3.5 by treating with triethyl amine. The precipitated 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (7-AMCA) is isolated(wet yield— 190gm).

(B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (190gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with

Berszothiazo ί-2-yi (Z)-2-meth.oxyimino-2-(2-ainmothia2'.oIe-4-yI) thioacetate (MAE ) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (102gm,Assay 95.5%>).

(C ) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at - 10 to - 15°C over a period of 1 Ominutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.13gm, Assay 95.4%)

Example(13) A) 245ml of methane sulphonic acid was mixed with 60.0mlof an azeotropic mixture composed of 70% Trimethyl borate and 30% methanol and solution was cooled to 10°C. 7- amino cephalosporanic acid (100 gm, 0.3676 mole) was slowly added in 30min and dissolve completely. Then additional 63ml of trimethyl borate azeotropic mixture was added slowly in 80-90 meanwhile maintaining the temperature at 10-12°C. The reaction mixture stirred for 60-90min and quenched the reaction mass by adding it to chilled water (1000ml) . Added aqueous ammonia solution (305 gm 20% ammonia in 695ml water) slowly over a period of 60-75min maintaining the temperature in the range of 0-10°C to attain a pH value of around 0.5 followed by adjusting the solution to 3.3 to 3.5 by treating with triethyl amine. The precipitated 7- Amino 3-methoxymethyl 3-cephem carboxylic acid (7-AMCA) is isolated(wet yield— 340gm).

(B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (340gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with

Benzothiazo l-2-yl (Z)-2-methoxyimino-2-(2-aminothiazole-4-yl) thioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (85gm,Assay 93.5%>).

(C ) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 23.60gm, Assay 93.2% )

Example(14)

A) 245ml of methane sulphonic acid was mixed with 60.0mlof an azeotropic mixture composed of 70% Trimethyl borate and 30% methanol and solution was cooled to 10°C. 7- amino cephalosporanic acid (100 gm,0.3676 mole) was slowly added in 30min and dissolve completely. Then additional 63ml of trimethyl borate azeotropic mixture was added slowly in 80-90 meanwhile maintaining the temperature at 10-12°C - The reaction mixture stirred for 60-90min and quenched the reaction mass by adding it to chilled methanol (1000ml) . Added triethyl amine (348 gm) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to attain a pH value of around 0.5 followed by adjusting the solution to 3.3 to 3.5 by treating with methanolic ammonia solution. The precipitated 7-Amino 3- methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 200 gm).

(B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (200gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z)-2-inethoxyimmo-2-(2-arainothia2:ole-4-y].)thioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).

(98gm,Assay 94.0%).

( C) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes. The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.20gm, Assay 93.6% )

Example(15) A) 1000ml of sulpholane was mixed with 225 gm methanol . Purge 360 gm BF3 gas at 30- 40°C in 60-90 min . Then charge 7-amino cephalosporanic acid (100 gm,0.3676 mole) at 45°C in single lot. The reaction mixture stirred for 60-90min at 48-50°C and quenched the reaction mass by adding it to chilled water (1000 ml) . Charge 1000ml methylene chloride , stir 10 min at 30°C .Separate the layers. Again Charge 1000ml methylene chloride , stir 10 min at 30°C .Separate the layers. Again Charge 1000ml methylene chloride , stir 10 min at 30°C .Separate the layers. Added aqueous ammonia solution slowly to the aqueous layer over a period of 60-75min maintaining the temperature in the range of 0-lOC to attain a pH value of around 0.5 followed by adjusting the pH of the solution attained 3.3 to 3.5. The precipitated 7- Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 320gm).

(B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (320gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with

Benzothiazoi-2-yi (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (99gm,Assay 95.5%).

(C ) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.00gm, Assay 95.2%>) ] Example(16)

A) 1000ml of sulpholane was mixed with 225 gm methanol . Purge 360 gm BF3 gas at 30- 40°C in 60-90 min . Then charge 7-amino cephalosporanic acid (100 gm,0.3676 mole) at 45°C in single lot. The reaction mixture stirred for 60-90min at 48-50°C and quenched the reaction mass by adding it to chilled water (1000 ml) . Charge 1000ml methylene chloride , stir 10 min at 30°C .Separate the layers. Again Charge 1000ml methylene chloride , stir 10 min at 30°C .Separate the layers. Again Charge 1000ml methylene chloride , stir 10 min at 30°C .Separate the layers. Added aqueous ammonia solution slowly to the aqueous layer over a period of 60-75min maintaining the temperature in the range of 0-lOC to attain a pH value of around 0.5 followed by adjusting the pH of the solution to 3.3 to 3.5. The precipitated 7- Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated (wet yield— 300gm).

(B) 7- Amino 3-methoxymethyl 3-cephem carboxylic acid (300gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with

Benzothiazol-2-yl (Z)-2-methoxyimino-2-(2-aniinothiazole'-4-yi)thioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (100gm,Assay 97.5%).

(C ) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes. The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.22gm, Assay 97.3% )

Example(17)

A) 1000ml of sulpholane was mixed with 225 gm methanol . Purge 360 gm BF3 gas at 30- 40°C in 60-90 min . Then charge 7-amino cephalosporanic acid (100 gm,0.3676 mole) at 45°C in single lot. The reaction mixture stirred for 60-90min at 48-50°C and quenched the reaction mass by adding it to chilled methanol (1000 ml) . Added methanolic ammonia solution slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to achieve pH value of around 0.5, Filtering the precipitated solid, followed by adjusting the pH of the filtrate to 3.3 to 3.5. The precipitated 7-Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 250gm).

(B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (250gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazoi-2-yi (Z)"2-methoxyimino-2-(2-aminothiazole~4~yl)thioaceiaie (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).

(100gm,Assay 95.1%).

(C ) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.04gm, Assay 94.5% )

Example(18)

A) 1000ml of sulpholane was mixed with 225 gm methanol . Purge 360 gm BF3 gas at 30- 40°C in 60-90 min . Then charge 7-amino cephalosporanic acid (100 gm,0.3676 mole) at 45°C in single lot. The reaction mixture stirred for 60-90min at 48-50°C and quenched the reaction mass by adding it to chilled methanol (1000 ml) . Added triethyl amine slowly over a period of 60-75 min maintaining the temperature in the range of 0-lOC to attain a pH value of around 0.5 followed by adjusting the pH of the solution to 3.3 to 3.5. The precipitated 7- Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 280gm). (B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (280 gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with

BenzothiazoI-2-yi (Z)"2~methoxyimino~2-(2~aminotMazole~4-yl)thioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (101gm,Assay 94.2%).

(C ) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.00gm, Assay 93.6% )

Example(19)

A) 1000ml of sulpholane was mixed with 225 gm methanol . Purge 360 gm BF3 gas at 30- 40°C in 60-90 min . Then charge 7-amino cephalosporanic acid (100 gm,0.3676 mole) at 45°C in single lot. The reaction mixture stirred for 60-90min at 48-50°C and quenched the reaction mass by adding it to chilled methanol (1000 ml) . Added methanolic ammonia solution (112 gm ammonia in 1000ml methanol) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to achieve pH value of around 0.5,Filtering the precipitated solid, followed by adjusting the pH of the filtrate to 3.3 to 3.5 by treating with triethyl amine. The precipitated 7-Amino 3-methoxymethyl 3-cephem carboxylic acid(7- AMCA) is isolated(wet yield— 200gm).

(B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (200 gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with

BenzothiazGl-2-yI (Z)"2~methoxyimino~2-(2~aminotMazole~4-yl)thioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (102gm,Assay 98.3%>). (C ) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.39gm, Assay 98.0%)

Example(20)

A) 1000ml of sulpholane was mixed with 225 gm methanol . Purge 360 gm BF3 gas at 30- 40°C in 60-90 min . Then charge 7-amino cephalosporanic acid (100 gm,0.3676 mole) at 45°C in single lot. The reaction mixture stirred for 60-90min at 48-50°C and quenched the reaction mass by adding it to chilled water (1000 ml) . Charge 1000ml methylene chloride , stir 10 min at 30°C .Separate the layers. Again Charge 1000ml methylene chloride , stir 10 min at 30°C .Separate the layers. Again Charge 1000ml methylene chloride , stir 10 min at 30°C .Separate the layers. . Added aqueous ammonia solution (360 ml 20% ammonia and 640 ml water ) slowly to the aqueous layer over a period of 60-75min maintaining the temperature in the range of 0-lOC to attain a pH value of around 0.5 followed by adjusting the pH of the solution to 3.3 to 3.5 by treating with triethyl amine. The precipitated 7- Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 310gm).

(B) 7- Amino 3-methoxymethyl 3-cephem carboxylic acid (310gm) Obtained in step (A) above is taken in a aqueous methanol and cooled to 15-20°C and treated with

Benzochiazo ί-2-yi (Z)-2-meth.oxyimino-2-(2-ainmothia2'.oIe-4-yI) thioacetate (MAE ) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (87.0gm,Assay 94.5%).

(C ) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.00gm, Assay 94.0% )

Example (21)

A) 1000ml of sulpholane was mixed with 225.0 gm methanol . Purge 360.0 gm BF3 gas at 30-40°C in 60-90 min . Then charge 7-amino cephalosporanic acid (100 gm,0.3676 mole) at 45°C in single lot. The reaction mixture stirred for 60-90min at 48-50°C and quenched the reaction mass by adding it to chilled methanol (1000 ml) . Added triethyl amine (580gm) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to attain a pH value of around 0.5 followed by adjusting pH of the solution to 3.3 to 3.5 by treating with methanolic ammonia solution. The precipitated 7- Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 180gm).

(B) 7- Amino 3-methoxymethyl 3-cephem carboxylic acid (180 gm) Obtained in step (A) above is taken in a aqueous methanol and cooled to 15-20°C and treated with

Benzothiazo ί-2- ί (Z)-2-meth.oxyimino-2-(2-ainmothia2'.oIe-4-yI)tWoacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (99.0gm,Assay 96.0%).

(C ) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.20gm, Assay 95.3%> ) Example (22)

(A) Added 7-Amino ce halosporanic acid (100gm,0.3676 mol) is added to mixture of methane sulphonic acid(500ml) and methanol(155ml) at a temperature ranging between 5°- 10°C. The reaction mixture stirred for l-2hours around 10-12° and quenched the reaction mass by adding it to chilled methano 1(1000ml). Added methanolic ammonia solution (126 gm in 1000ml) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to achieve pH value of around 0.5, filtering the precipitated solid, followed by adjusting the pH of the filtrate to 3.3 to 3.5 by treating with Diethyl amine. The precipitated 7-Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 158gm).

(B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (158gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z)"2-methoxyimino-2-(2-aminothiazole~4~yl)thioaceiate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (lOlgm, Assay 98.2%).

(C) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in

dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.39gm, Assay 98.0% ) Example(23)

A) 245ml of methane sulphonic acid was mixed with 60.0mlof an azeotropic mixture composed of 70% Trimethyl borate and 30% methanol and solution was cooled to 10°C. 7- amino cephalosporanic acid (100 gm,0.3676 mole) was slowly added in 30min and dissolve completely. Then additional 63ml of trimethyl borate azeotropic mixture was added slowly in 80-90 meanwhile maintaining the temperature at 10-12°C . The reaction mixture stirred for 60-90min and quenched the reaction mass by adding it to chilled methanol (1000ml) . Added methanolic ammonia solution (126 gm in 1000ml) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to achieve pH value of around 0.5, filtering the precipitated solid, followed by adjusting the pH of the filtrate to 3.3 to 3.5 by treating with Diisopropylamine. The precipitated 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (7-AMCA) is isolated (wet yield— 180gm).

(B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (180gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z)-2 ^» methoxyimino-2-(2 ^» amiiiothiazole-4-yl)thioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).

(102gm,Assay 95.2%). (C) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in

dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes.

The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.07gm, Assay 95.2% )

Example(24)

A) 1000ml of sulpholane was mixed with 225 gm methanol . Purge 360 gm BF3 gas at 30- 40°C in 60-90 min . Then charge 7-amino cephalosporanic acid (100 gm,0.3676 mole) at 45°C in single lot. The reaction mixture stirred for 60-90min at 48-50°C and quenched the reaction mass by adding it to chilled methanol (1000 ml) . Added methanolic ammonia solution (112 gm ammonia in 1000ml methanol) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to achieve pH value of around 0.5, filtering the precipitated solid, followed by adjusting the pH of the filtrate to 3.3 to 3.5 by treating with tetramethylguanidine. The precipitated 7-Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated (wet yield— 190gm).

(B) 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (190gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z)-2-methoxyiinino-2-(2-aminothia x)ie-4-yl)thioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).

(101gm,Assay 98.1%).

(C) Cefpodoxime acid (20.0gm,0.0468mole) obtained in Step B dissolved in dimethylacetamide (100 ml) and cooled to ( -) 1 0°C. (6.05gm,0.0398mol) of DBU was added drop wise maintaining the temperature in the range of-10 to -15°C in 10 min , stir for 5 minutes. Anhydrous sodium acetate (0.77gm,0.00939 mole) is added and stirred for 10 minutes , followed by addition of 1-iod oethylisopropylcarbonate(13.29 gm,0.0515 mole) at -10 to -15°C over a period of lOminutes. The reaction mixture was stirred for 30 min . The reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.09gm, Assay 98.0% )