The present invention is in the field of chemistry and more particularly the present invention relates to the preparation of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) which is utilized for the preparation of cefpodoxime acid of formula (I), in a very safe, simple, economical, user-friendly and in an industrially viable manner.

H2N^.S
COOH
Formula (V)

'CH<

HoN

NH .S.
'CH-
OCH3 o Y "3
COOH Formula (I)

Background of the invention
Cefpodoxime acid of formula (I), is chemically known as 7-[ (Z)-2-(2» Amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid which is disclosed in US 4,409,215 (Fujisawa). Although cefpodoxime acid is not suitable for oral administration, its ester derivative, 1-(isoproxycarbonyloxyl)ethyl ester i.e. cefpodoxime proxetil of formula II which is disclosed in US 4,486,425 (Sankyo), is a valuable orally administered antibiotic characterized by high broad spectrum activity against gram positive and gram negative microorganisms. It is a potent antibiotic and is of great therapeutic interest in the treatment of acute bronchitis, exacerbations, pneumonia, sinusitis, recurrence of chronic tonsillitis, pharyngitis and acute otitis media.


HoN

NH ^S.
1 o^-J^°
OCH3
A. 0

Formula (II)
In prior art, cefpodoxime acid of formula (I) is prepared by reacting 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) with 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-benzothiazolyl thioester of formula (VI), in the presence of a solvent and a base.


HoN
HoN

T* p
O-
y\-£Q
'Chi

Formula (V)

Formula (VI)

7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) is a precursor of cefpodoxime acid of formula (I). There are several methods in the prior art for the preparation thereof, involving the use of 7-Amino cephalosporanic acid (7-ACA) of formula (I'll) as an intermediate.

HoN
0COCH3
COOH

Formula (III)

However, prior arts known processes has its own problems, for example each yields only moderate quantities of the desired product. A large amount of by-products are produced during these processes due to the production of lactone compound of formula (VII) (resulting from the cyclisation of the carboxy group and the 3-position acetoxymethyl group of the starting material 7-ACA) or due to the decomposition of the p-lactam ring. These by-products reduce the yield and interfere with the purification process.


HoN

Formula (VII)
It has been found that the preparation of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) from 7-Amino cephalosporanic acid (7-ACA) of formula (III) provides low yield and quality. This undesired quality of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) effects on the quality of Cefpodoxime acid of formula (I).
Formula (IV)
In prior art, 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) can also be prepared by using another intermediate i.e. deacetyl-7-aminocephalosporanic acid (D-7-ACA) or 7-amino-3-hydroxymethyl-3-cephem carboxylic acid (7-HACA) of formula (IV).


US 4,008,231 (Eli Lilly) discloses a process for preparing a 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) comprises reaction of a deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV) with p-nitrobenzylchloroformate in the presence of solvent to obtain 7-(4-nitrobenzyloxycarbamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid which is treated with trifluoroacetic anhydride in the presence of solvent to obtain desired trifluoroacetate intermediate. A foam resulted which is treated with methanol, trimethyl orthoformate, potassium iodide, and potassium hydrogen phosphate in the presence solvent (acetonitirle) to obtain 7-(4-nitrobenzyloxycarbonylamino)-3-methoxymethyl-3-cepherh-4-carboxylic acid. The 7-substituent then can be cleaved by using Zinc Dust and thiophenol to obtain 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V). This process involves higher number of chemical steps and results in low yield and quality.
US 5,597,914 (Biochemie) discloses a process for the preparation of a 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V), by reacting a deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV) in a solvent (an ester of an organic carboxylic acid, dimethyl carbonate, dipropyl carbonate, nitromethane, sulpholane, dichloromethane, dimethyl sulphoxide a nitroalkane, a chlorinated hydrocarbon or a mixture thereof) with an etherification agent such as dimethoxycarbenium-tetrafluoroborate which can be utilized either an isolated form or prepared insitu in the reaction. This process requires the use of boron trifluoride which is hazardous, costly and difficult to handle at large scale. BF3 also is relatively expensive, making the process not viable industrially. Moreover, this process gives relatively good yields (approximately 62-79%), but still have the problem of low product purity. This process leads to form inner lactone of compound of formula (VII) 15% during reaction which lower the quality of the product and reduces the yield.

WO 2017/153824 A1 (Dhanuka Laboratories Ltd) discloses a process for alkylating hydroxymethyl group at position- 3 of cephalosporins (AMCA), the said process comprising of reacting 3- hydroxymethyl cephalosporin's (D-7ACA) with a suitable alkylating agent in a suitable organic solvent (selected from a group consisting of dialkyl carbonate, dialkyl dicarbonate, acetonitrile, dichloromethane, sulpholane, and mixtures thereof) in presence of an organic acid. The drawbacks of this process are given below:
i) This process involves high boiling class-2 solvents which are toxic in nature.
ii) Recovery of these solvents are difficult and generate high load on Effluent Treatment Plant (ETP).
iii) The use of these solvent requires high energy load.
iv) High cost involves for recovery and recycling for these solvents
v) Testing of these solvents itself need a separate analytical method as these solvents does not elute with common organic solvents such as acetone, ethylacetate, methanol, toluene, dichloromethane and acetonitrile etc..
vi) As these high boiling solvents are having tendency to carry forwarded with the product. Therefore, tedious to remove these solvents from product.
In addition, prior art methods are associated with formation of varying amounts of impurities which give the product in low purity or quality, rendering such method less efficient.
7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) which is prepared as per prior art methods leads to provide cefpodoxime acid having low yield and quality at an industrial scale. To make intermediate with
6
t - i- if ._ •■> rrv-i: ■* t 7 «•■ "2 c

lower impurity and removal of carry forward impurities require tedious purification process at final API or its intermediate stages.
Pharmaceutical compounds are required in highly pure form because of the fear of unknown and potentially harmful effects of impurities. For purposes of patient1 safety, it is highly desirable to limit the amount of impurities present in any medicament administered to a patient. This is achieved by either devising a process for or by additional purification steps like chromatography or recrystallization etc. The purity of intermediates and raw materials is essential for obtaining the target pharmaceutical compounds in high yield and purity.
There still remains a need to provide an efficient and better process for the preparation of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) which is simple, cost-effective, commercially viable, sustainable and eco-friendly.
We have found that when the reaction of deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV) is carried out with an alkylating agent and an acid in the absence of solvent for the preparation of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V), overcomes the problem associated with prior art processes.
As discussed above, none of the prior arts disclose reaction of deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV) with an alkylating agent and an acid in the absence of solvent for the preparation of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V). Hence, we focused our research to develop an efficient and better process for the preparation of a desired quality of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) which is utilized for the preparation of Cefpodoxime acid of formula (I) with substantially fair operational safety,
7 KI J*- *'>--> n-IT- i T - a c

satisfactory yield and high chemical purity, that would make the process more distinct, cost effective and successful at industrial and commercial level.
The process of present invention is simple, inexpensive and reproducible and feasible at an industrial scale.
The present invention provides remarkable advantages in the industrial processes for the production of cefpodoxime acid of formula (I). In fact, the process of the invention provides good quality cefpodoxime acid of formula (I) in yields quite comparable with those expected with the prior art methods.
Moreover, the cefpodoxime acid of formula (I) can easily be converted into the corresponding pharmaceutically acceptable salt or ester thereof, preferably into cefpodoxime proxetil of formula (II), by using conventional techniques known to those skilled in the art.
Objective of the invention
The main object of the present invention is to provide a process for the preparation of a cefpodoxime acid of formula (I) through its intermediate i.e. 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V), which is very safe, simple, economical, user-friendly and commercially viable.
Another objective of the present invention is to provide a process for the preparation of a 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvent(s) which makes the present invention more safe and eco-friendly as well.
The process of the present invention provides a simple and inexpensive process for preparing 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-
8
Baa. * S, -ft** «&. ■&. „JL„ fi«. Am. W 'Wfc J- •&. J - mmg. t_p

AMCA) of formula (V) with reduces formation of lactone impurity of deacetyl-7-aminocephalosporanic acid (D-7-ACA) to less than 0.2%.
Yet another objective of the present invention is to provide a process for the preparation of a cefpodoxime acid of formula (I) in a greater yield with higher chemical purity or quality.
Summary of the invention
The present invention provides an economically viable industrial eco-friendly process for the preparation of cefpodoxime acid of formula (I).
Accordingly, the present invention provides a process for the preparation of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V),

H9N
COOH Formula (V)

which comprises the steps of:
i. reacting deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV) with an alkylating agent and an acid in the absence of solvent;
i. quenching the reaction mass of step (i) with water;
ii. optionally washing the reaction mass with a water immiscible solvent; and
v. precipitating 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) by adjusting the pH of the aqueous solution as obtained from step (ii) or (iii) with a base
TQ"tf\ FfcC:-!:- fcl-T 1.1 - 1 > - "> *> 1: y 1 7 '■ Z G

The above process is illustrated in the following synthetic scheme:


Alkylating Agent Acid

HoN

Formula (V)

Alternatively, the present invention provides a process for the preparation of cefpodoxime acid of formula (I),

HoN

OCH3 o

N^^^ CH

COOH
Formula (I)
which comprises the steps of:
i. reacting deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV)
with an alkylating agent and an acid in the absence of solvent; i. quenching the reaction mass of step (i) with water; ii. optionally washing the reaction mass with a water immiscible solvent; v. precipitating 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-
AMCA) of formula (V) by adjusting the pH of the aqueous solution as
obtained from step (ii) or (iii) with a base; and v. reacting 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of
formula (V) with 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-
10

n.c;-u-: U-T
SW £«_ E».. B: D.' «D».

1: 1:

■fci-. £*.

o> m T 1- % y

benzothiazolyl thioester of formula (III) in the presence of a base and a solvent to obtain cefpodoxime acid of formula (I).
The above process is illustrated in the following synthetic scheme:

H2N^ ^S. ^OH Alkylating Agent Acid "XX
COOH Formula (IV)
COOH Formula (V)

.o.

CH<

N
Solvent Base

H2N

^

-CO

HoN
>=N

O

CH3 Formula (VI)

OCH3 tS T
COOH

CH-

Formula (I)

Detailed description of the invention
Accordingly in an embodiment of the present invention provides a process for the preparation of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V),
COOH
H2l\k ^S
Formula (V)
which comprises the steps of:
11

s=e &=.-. s=«--, a. s. cJ&>,

1- 1 - t \>

-> 0 1: J'

1 7

i. reacting deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV) with an alkylating agent and an acid in the absence of solvent;
ii. quenching the reaction mass of step (i) with water;
iii. optionally washing the reaction mass with a water immiscible solvent;and
iv. precipitating 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) by adjusting the pH of the aqueous solution as obtained from step (ii) or (iii) with a base
The step i) involves a reaction of deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV) with an alkylating agent in the presence of an acid. The alkylating agent is selected from the group consisting of trialkyl orthoformate such as trimethyl orthoformate; trialkyl borate such as trimethyl borate; trialkyl orthoacetate such as trimethyl orthoacetate; methyl sulfate, methyl phosphate and dimethyl sulfate or mixture thereof. The acid is selected from the group consisting of alkyl or aryl sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, sulfuric acid, polyphosphoric acid and boron trifluoride. The reaction may be carried out at -50°C to+40°C. Most preferably at 0°C to 35°C.
The step ii) involves quenching the reaction mass of step (i) with water. The reaction may be carried out at -5°C to 30°C.
The reaction can also be performed with or without washing.
The step iii) involves washing of reaction masis with a water immiscible solvent. The water immiscible solvent is selected from the group consisting of dichloromethane, methyl acetate, ethyl acetate, t-butyl acetate, hydrocarbon such as toluene, xylene, n-butanol, monoglyme, diglyme or mixture thereof.This step involves separation of layers. The aqueous layer is subjected for further reaction.
12
£■».. G->, 8. 1L s&t Jk A »& fc=- £=. •Sup' mSk ■ f *6»- /" "• „rf %_(■

The step iv) involves precipitation of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) by adjusting the pH of the solution as obtained from step (ii) or (iii) with a base. The base is selected from the group consisting of inorganic base, organic base or mixture thereof. The inorganic base is selected from the group of alkali carbonate such as sodium carbonate, potassium carbonate, or alkali bicarbonate such as sodium bicarbonate, potassium bicarbonate, or alkali hydroxide such as sodium hydroxide, potassium hydroxide, or alkali methoxide such as sodium methoxide, potassium methoxide; aqueous ammonia or mixture thereof. The organic base is selected from the group consisting of dialkylamine such as diethylamine, or trialkyl amines such as triethyl amine, trimethyl amine, diisopropyl arnine etc., or dialkyi anilines such as dimethyl aniline or dimethylaminopyridine or N-methyl morpholine or mixture thereof. Most preferably, aqueous ammonia. The reaction may be carried out at 0°C to 40°C. Most preferably at 5°C to 35°C.
The resultant compound i.e. 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) of the present invention may have the purity greater than 97-5 % and lactone impurity less than 0.2%.
Formula (I)
which comprises the steps of:
13
FIE" i: U; T 11- 1 ->■ -. -> ffr 1 "?■ 1- ? ■ 2 C'
The present invention provides a process for the preparation of cefpodoxime acid of formula (I),


i. reacting deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV) with an alkylating agent and an-acid in the absence of solvent;
ii. quenching the reaction mass of step (i) with water;
iii. optionally washing the reaction mass with a water immiscible solvent;
iv. precipitating 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) by adjusting the pH of the aqueous solution as obtained from step (ii) or (iii) with a base; and
v. reacting 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) with 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-benzothiazolyl thioester of formula (III) in the presence of a base and a solvent to obtain cefpodoxime acid of formula (I).
The step i) involves a reaction of deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV) with an alkylating agent in the presence of an acid. The alkylating agent is selected from the group consisting of trialkyl orthoformate such as trimethyl orthoformate; trialkyl borate such as trimethyl borate; trialkyl orthoacetate such as trimethyl orthoacetate; methyl sulfate, methyl phosphate and dimethyl sulfate or mixture thereof. The acid is selected from the group consisting of alkyl or aryl sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, sulfuric acid, polyphosphoric acid and boron trifluoride. The reaction may be carried out at -50°C to +40°C. Most preferably at 0°C to 35°C.
The step ii) involves quenching the reaction mass of step (i) with water. The reaction may be carried out at -5°C to 30°C.
The reaction can also be performed with or without washing.
The step iii) involves washing of reaction mass with a water immiscible solvent. The water immiscible solvent is selected from the group consisting of dichloromethane, methyl acetate, ethyl acetate, t-butyl acetate, hydrocarbon
14
I. U T . 1 1 _ t O - •*> n % T- 1 T " 2 C

such as toluene, xylene, n-butanol, monoglyme, diglyme or mixture thereof.This step involves separation of layers. The aqueous layer is subjected for further reaction.
The step iv) involves precipitation of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) by adjusting the pH of the solution as obtained from step (ii) or (iii) with a base. The base is selected from the group consisting of inorganic base, organic base or mixture thereof. The inorganic base is selected from the group of alkali carbonate such as sodium carbonate, potassium carbonate, or alkali bicarbonate such as sodium bicarbonate, potassium bicarbonate, or alkali hydroxide such as sodium hydroxide, potassium hydroxide, or alkali methoxide such as sodium methoxide, potassium methoxide; aqueous ammonia or mixture thereof. The organic base is selected from the group consisting of dialkylamine such as diethylamine, or trialkyl amines such as triethyl amine, trimethyl amine, diisopropyl amine etc., or dialkyi anilines such as dimethyl aniline or dimethylaminopyridine or N-methyl morpholine or mixture thereof. Most preferably, aqueous ammonia. The reaction may be carried out at 0°C to 40°C. Most preferably at 5°C to 35°C.
The step v) involves condensation of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) with 2-[2-aminothiazol-4-yJ]-2-syn-methoxyimino acetic acid-2-benzothiazolyl thioester of formula (III) in the presence of a base and a solvent to obtain cefpodoxime acid of formula (I). An organic base is selected from the group consisting of triethylamine, pyridine, N-methylpiperidine, 1,8-diazabicycloundecene, 4-dimethylaminopyridine or mixtures thereof, more preferably triethylamine. The solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, acetonitrile, dichloromethiane, toluene, dioxane, isopropyl ether, dimethylformamide, N-Methyl-2-pyrrolidon, ethyl acetate, tetrahydrofuran, dimethylacetamide, monglyme, diglyme, water and the like or mixture thereof. Most preferably
15
■ U- T 1 ■ 1 _ t ^ _ ■•> Ci 1 7 1 "? ■ 3C
as- B &. -Bar, «&.. Jfa.-.-, B&, fi_ Bb*. ■<-»?• ■£.-. X. o&- s* - m*t,-\*Jf

methanol or mixture of methanol and water. The reaction may be carried out at 0°C to 20°C. Most preferably at 5°C to 15°C.
In yet another embodiment of the present invention, process for preparation of a cefpodoxime acid of formula (I) may also be extended further in the making of cephalosporin antibiotics such as cefpodoxime proxetil of formula (II) by conventional methods.
The present invention includes pharmaceutical compositions comprising cefpodoxime proxetil produced by the process of the present invention, together with at least one pharmaceutical^ acceptable excipient.
The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.
Examples:
EXAMPLE-1: Preparation of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-A MCA) of formula (V)
Trimethylorthoformate (80.0 gm) and deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV) (50.0 gm) was stirred in the RB flask at 0° to 10°C. Methanesulfonic acid (MSA, 100 gm) was added slowly to the reaction mass and stirred and maintained at 30° to 34°C. After completion of the reaction, the reaction mass was quenched into brine solution then washed with ethyl acetate and separated the layers. The aqueous layer was subjected for pH adjustment 3.0-3.5 with ammonium hydroxide solution to precipitate the product which was isolated by filtration and drying. 65 g of wet material was obtained which was used for condensation step. HPLC purity: 98.5%.
16
*\EZI u. "P i i. - i -> - ~> n, * 7 ■ IT - z.c
IW- En.. &=, £_. B. mftu-^ m&k *£. £&„ £B. !&m> W rot. f (fi *' - mf \m£

EXAMPLE-2: Preparation of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V)
Trimethylorthoformate (50.0 gm) and deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV) (50.0 gm) was stirred in the RB flask at 0° to 10°C. Methanesulfonic acid (MSA, 90.0 gm) was added slowly to the reaction mass, stirred and maintained at 30° to 34°C. After completion of the reaction, the reaction mass was quenched into brine solution then washed with dichloromethane and separated the layers. The aqueous layer was subjected for pH adjustment 3.0-3.5 with ammonium hydroxide solution to precipitate the product which was isolated by filtration and drying. 62 g of wet material was obtained which was used for condensation step. HPLC purity: 98.4%.
EXAMPLE-3: Preparation of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V)
Trimethylorthoformate (50.0 gm) and deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV) (50.0 gm) was stirred in the RB flask at 0° to 10°C. Sulfuric acid (100.0 gm) was added slowly to the reaction mass, stirred and maintained at 30° to 34°C. After completion of the reaction, the reaction mass was quenched into brine solution then washed with dichloromethane and separated the layers. The aqueous layer was subjected for pH adjustment 3.0-3.5 with ammonium hydroxide solution to precipitate the product which was isolated by filtration and drying. 60 g of wet material was obtained which was used for condensation step. HPLC purity: 97.7%.
EXAMPLE-4: Preparation of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V)
Trimethylorthoformate (80.0 gm) and deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV) (50.0 gm) was stirred in the RB flask at 0° to

10°C. Sulfuric acid (100.0 gm) was added slowly to the reaction mass, stirred and maintained at 30° to 34°C. After completion of the reaction, the reaction mass was quenched into brine solution. The reaction mass was subjected for pH adjustment 3.0-3.5 with ammonium hydroxide solution to precipitate the product which was isolated by filtration and drying. 61.5 g of wet material was obtained which was used for condensation step. HPLC purity: 98.1,%.
EXAMPLE-5: Preparation of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V)
Trimethylorthoformate (50.0 gm) and deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV) (50.0 gm) was stirred in the RB flask at 0° to 10°C. Methanesulfonic acid (MSA, 100 gm) was added slowly to the reaction mass and stirred and maintained at 30° to 34°C. After completion of the reaction, the reaction mass was quenched into brine solution. The reaction mass was subjected for pH adjustment 3.0-3.5 with ammonium hydroxide solution to precipitate the product which was isolated by filtration and drying. 63 g of wet material was obtained which was used for condensation step. HPLC purity: 97.9%.
EXAMPLE-6: Preparation of cefpodoxime acid of formula (I)
65 g of wet 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) which was obtained in Example-1 and 58 g of 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-benzothiazolyl thioester (MAEM) were added in 205 ml of methanol at 20°C to 30°C. The reaction mixture was cooled to 0°C to 15°C and 16.68 g of triethylamine was added dropwise into it. The solution was stirred at 10°C to 18°C until the reaction was completed. After the reaction completion, the reaction mass poured into the water and adjusted the pH of the reaction mass in the range of 5.0 to 6.0 with hydrochloric acid. The reaction mass was stirred for 20-30 minutes and filtered it for removing MBT. The filtrate was

charcoalized and filtered the mass through hyflo bed and washed with water. The pH of the filtrate solution was adjusted from dilute HCI at 2.0-2.1 and stirred at 17°C to 20°C for 3-4 hrs. The solid was filtered, washed with water and finally with 100 ml of acetone. It was dried to get 56 g of the title compound. HPLC purity: 98.8%
EXAMPLE-7: Preparation of cefpodoxime acid of formula (I)
62 g of wet 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-
AMCA) which was obtained in Example-2 and 57 g of 2-[2-aminothiazol-4-yl]-2-
syn-methoxyimino acetic acid-2-benzothiazolyl thioester (MAEM) were added in
200 ml of methanol and 65 ml of water at 20°C to 30°C. The reaction mixture was
cooled to 0°C to 15°C and 17 g of triethylamine was added dropwise into it. The
solution was stirred at 10°C to 18°C until the reaction was completed. After the
reaction completion, the reaction mass poured into the water and adjusted the
pH of the reaction mass in the range of 5.0 to 6.0 with hydrochloric acid. The
reaction mass was stirred for 20-30 minutes and filtered it for removing MBT. The
filtrate was charcoalized and filtered the mass through hyflo bed and washed with
water. The pH of the filtrate solution was adjusted from dilute HCI at 2.0-2.1 and
stirred at 17°C to 20°C for 3-4 hrs. The solid was filtered, washed with water and
finally with 100 ml of acetone. It wao dried to get 57 g of the title compound.
HPLC purity: 98.6%
EXAMPLE-8: Preparation of cefpodoxime acid of formula (I)
63 g of wet 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-
AMCA) which was obtained in Example-5 and 59 g of 2-[2-aminothiazol-4-yl]-2-
syn-methoxyimino acetic acid-2-benzothiazolyl thioester (MAEM) were added in
195 ml of methanol at 20°C to 30°C. The reaction mixture was cooled to 0°C to
15°C and 16.8 g of triethylamine was added dropwise into it. The solution was
stirred at 10°C to 18°C until the reaction was completed. After the reaction

completion, the reaction mass poured into the water and adjusted the pH of the reaction mass in the range of 5.0 to 6.0 with hydrochloric acid. The reaction mass was stirred for 20-30 minutes and filtered it for removing MBT. The filtrate was charcoalized and filtered the mass through hyflo bed and washed with water. The pH of the filtrate solution was adjusted from dilute HCI at 2.0-2.1 and stirred at 17°C to 20°C for 3-4 hrs. The solid was filtered, washed with water and finally with 100 ml of acetone. It was dried to get 54 g of the title compound. HPLC purity: 98.7%
Substantial Advantages and Industrial applicability
i. The process of the present invention is very safe, simple and gives higher purity and greater yield of an intermediate i.e. 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) as well as of cefpodoxime acid of formula (I).
ii. The process of the present invention avoids use of organic solvents during alkylation and excess usages of reagent(s), thereby promoting green chemistry and ensuring a cleaner surrounding by putting less load on environment.
iii. The process of the present invention is a simple process, which avoids more number of operations, thus resulting in shortening of reaction time and lowering of labor.

We claim:
A process for the preparation of 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V),

H2M S
'CH-
. . COOH
Formula (V)
which comprises the steps of:
i. reacting deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV) with
an alkylating agent and an acid in the absence of solvent; ii. quenching the reaction mass of step (i) with water; iii optionally washing the reaction mass with a water immiscible solvent; and iv. precipitating 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of
formula (V) by adjusting the pH of the aqueous solution as obtained from step
(ii) or (iii) with a base.
The process as claimed in claim 1, wherein the alkylating agent in step (i) is selected from the group consisting of trialkyl orthoformate such as trimethyl orthoformate; trialkyl borate such as trimethyl borate; trialkyl orthoacetate such as trimethyl orthoacetate; methyl sulfate, methyl phosphate and dimethyl sulfate or mixture thereof.
The process as claimed in claim 1, wherein the acid in step (i) is selected from the group consisting of alkyl or aryl sulfonic acid such as methanesulfonic acid,

ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, sulfuric acid, polyphosphoric acid and boron trifluoride.
The process as claimed in claim 1, wherein the water immiscible solvent in step (iii) is selected from the group consisting of dichloromethane, methyl acetate, ethyl acetate, t-butyl acetate, hydrocarbon such as toluene, xylene, n-butanol, monoglyme, diglyme or mixture thereof.
The process as claimed in claim 1, wherein the base in step (v) is selected from
the group consisting of sodium carbonate, potassium carbonate, sodium
bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide,
sodium methoxide, potassium methoxide, aqueous ammonia, diethylamine,
triethylamine, trimethylamine, diisopropylamine, dimethylaniline,
dimethylaminopyridine, N-methylmorpholine or mixture thereof.
The process as claimed in claim 1, further comprising step of reacting 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of formula (V) with 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-benzothiazolyl thioester of formula (III) in the presence of a base and a solvent to obtain cefpodoxime acid of formula (I).
The process as claimed in claim 6, wherein the organic base is selected from the group consisting of triethylamine, pyridine, N-methylpiperidine, 1,8-diazabicycloundecene, 4-dimethylaminopyridine or mixtures thereof.
The process as claimed in claim 6, wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, acetonitrile, dichloromethane, toluene, dioxane, isopropyl ether, dimethylformamide, N-Methyl-2-pyrrolidon, ethyl acetate, tetrahydrofuran, dimethylacetamide, monglyme, diglyme, water or mixture thereof.

A process for the preparation of cefpodoxime acid of formula (I),
H2N
/==N O

NH
J-"^J-^°*
N
OCH3 O' ""f" ' "CH3
COOH Formula (I)

which comprises the steps of:
i. reacting deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV) with
an alkylating agent and an acid in the absence of solvent; ii. quenching the reaction mass of step (i) with water; iii optionally washing the reaction mass with a water immiscible solvent; iv. precipitating 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of
formula (V) by adjusting the pH of the aqueous solution as obtained from step
(ii) or (iii) with a base; and v. reacting 7-amino-3-methoxymethyl-3-cephem carboxylic acid (7-AMCA) of
formula (V) with 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-
benzothiazolyl thioester of formula (III) in the presence o^a base and a solvent
to obtain cefpodoxime acid of formula (I).