A PROCESS FOR THE PREPARATION OF CEFPODOXIME ACID AND ITS
INTERMEDIATE THEREOF
Field of the invention
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 (1), in a very safe, simple,
economical, user-friendly and in an industrially viable manner.
Formula (V) Formula (I)
Background of the invention
Cefpodoxime acid of formula (I), is chemically known as 7 -[ (Z)-2-(2-
Am ino-4-thiazolyl)-2 -(methoxyimino )acetamide ]-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.
2
IPO DELHI 28-04-2016 1s:sz
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.
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 ttie use of. 7 -Amino
cephalosporanic acid (7 -ACA) of formula (Ill) as an intermediate.
Formula (Ill)
3
16:52
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 ~-lactam ring. These by-products reduce the
yield and interfere with the purification process.
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 (Ill) 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).
In prior art, 7-amino 3-methoxymethyl-3-cephem carboxylic acid (7-AMCA)
of formula (V) can c;tlso be prepared by using another intermediate i.e. deacetyl-
7-aminocephalosporanic acid (0-7-ACA) or 7-amino 3-hydro:Xymethyl-3-cephem .
carboxylic acid (7 -HACA) of formula (IV).
Formula (IV)
4
IPO DELHI 28-04-2016
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-3-9ephem-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-cephem-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 ~lso 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.
5
-IPO DELHI 28-04-2016 16:52
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
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
patient' 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 in the presence of solvent and a proton acid 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 alkylating agent in the
6
IPO DELHI 28-04-2016
presence of proton acid and a 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,
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 (1). 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)
7
IPO DELHI 28-04-2016 15:52 .;::'
of formula (V), which would be easy to implement on commercial scale, and to
avoid excessive use of reagent(s) and organic solvent(s) and to avoid hazardous
and risky solvents or reagents, 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-
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 ecofriendly
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),
Formula (V)
which comprises the steps of:
i. reacting deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV)
with an alkylating agent in the presence of a proton acid and a solvent;
8
ii. quenching the reaction mass of step (i) with water and inorganic halide;
iii. optionally separating the aqueous layer; 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 above process is illustrated in the following synthetic scheme:
H N S
Alkylating Agent H2N '1---f~S
2o}=r' ~l OH ___P_ ro_to_n_A_c_id____ o~N .... o o ..... CH3
~ Solvent
COOH COOH
Formula (IV) Formula (V)
Alternatively, the present invention provides a process for the preparation
of cefpodoxime acid of formula (I),
Formula (I)
which comprises the steps of:
i. reacting deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV)
with an alkylating agent in the presence of a proton acid and a solvent;
ii. quenching the reaction mass of step (i) with water and inorganic halide;
2 8 - 0.4 - 2 0 1 6
9
1 c.• ·· r ·;. .... 'fJ • J . .:;;,
iii. optionally separating the aqueous layer;
iv. precipitating ?-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 (Ill) 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'r--f~S
~N .... .o OH
0
COOH
Formula (IV)
Alkylating Agent
Proton Acid
Solvent
Formula (V)
COOH
Formula (I)
Detailed description of the invention
Accordingly in an embodiment of the present invention provides a process
for the preparation of ?-amino 3-methoxymethyl-3-cephem carboxylic acid (7-
AMCA) of formula (V),
10
IPD DELHI 28-04-2016 15:52
l -
Formula (V)
which comprises the steps of:
i. reacting deacetyl-7 -aminocephalosporanic acid (D-7 -ACA) of formula (IV)
with an alkylating agent in the presence of a proton acid and a solvent;
ii. quenching the reaction mass of step (i). with water and inorganic halide;
iii. optionally separating the aqueous layer; 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 a proton
acid and a solvent. The alkylating agent is selected from the group consisting of
trialkyl orthoformate such as trimethylorthoformate thereof.The proton acid is
selected from the group consisting of alkyl or aryl sulfonic acid such as
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
naphthalenesulfonic acid. The solvent is selected from the group consisting of
esters of organic carboxylic acids such as formic acid methyl ester, formic acid
ethyl ester; esters of carbonic acid such as dimethyl carbonate, dipropyl
carbonate; nitriles such as acetonitrile, propionitrile,. benzonitrile, malonitrile;
nitroalkanes such as nitromethane, nitroethane, nitropropane; organic carboxylic
acids and esters thereof such as acetic acid, propionic acid, trifluoroacetic acid,
and esters. thereof; ketones such as acetone, methyl ethyl ketone, methyl
isobutyl ketone, acetophenone; halogenated alkanes such as dichloromethane,
11
IPO DELHI 28-0~-2816 16:52
chloroform, dichloroethane, carbon tetrachloride; halogenated alkenes such as
dichloroethylene, trichloroethylene; acid amides such as formamide,
dimethylformamide, acetamide; ethers such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, aromatic hydrocarbons
. such as benzene, toluene, chlorobenzene, nitrobenzene; alkanes such as nhexane,
heptane, alicyclic compounds such as cyclohexane; sulfolane; dimethyl
sulfoxide or mixture thereof.The reaction may be carried out at 06C to 30°C.
Most preferably at 15°C to 25°C.
The step ii) involves quenching the reaction mass of step (i) with water
and inorganic halide. The inorganic halide is selected from the group consisting
of sodium chloride, potassium chloride or mixture thereof. The reaction may be
carried out at -5°C to 15°C.
The step iii) involves separation of aqueous layer, optionally. When water
miscible solvent is utilized in step (I), aqueous solution is directly used for next
step without any layer separation.
The step iv) involves precipitation of 7 -amino 3-methoxyr:nethyl-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 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 triethylamine, trimethylamine, diisopropyl amine etc., or
dialkyl anilines such as dimethyl aniline or dimethylaminopyridine or N-methyl
12
IPO DELHI 28-84-2016 16:·52
TOn
J.. lr 'W1'
morpholine or mixtur e thereof. Most perferably, aqueous ammonia. The reaction
may be carried out at ooc to 40°C. Most preferably at soc to 35°C.
The resultan
carboxylic acid (7 -A
t compound i.e. 7 -amino 3-methoxymethyl-3-cephem
MCA) of formula (V) of the present invention may have the
purity greater than 99 .5 % and lactone impurity less than 0.2%.
Following is t
methoxymethyl-3-cep
he comparison of the result of preparation of 7 -amino 3-
hem carboxylic acid (7-AMCA) of formula (V) as prepared
by the present invent ion vis-a-vis US 5,597,914 by the process as disclosed in
prior art.
Table-01
S.No Pr ocess Yield(%)*
1 Preparation by process 61-79
disclosed in U s 5,597,914
2 Preparation by present invention 82
*on dry basis
HPLC
Purity{%)
92-94
98-98.5
Lactone
Impurity(%)
0.2 to 0.5
Less than 0.2
The results cle arly depict that when 7 -amino 3-methoxymethyl-3-cephem
MCA) of formula (V) is prepared by using deacetyl-7-
c acid (D-7-ACA) of formula (IV), significantly reduces the
carboxylic acid (7-A
ami~ocephalosporani
.lactone impurity.
The present invention provides a precess for the preparation of
cefpodoxime acid of f ormula (1),
13
n~t:::i' UcT·
b# a- a.... .11: £•..!!. 28-04-'2 016 16:52
Formula (I)
which comprises the steps of:
i. reacting deacetyl-7 -aminocephalosporanic acid (D-7 -ACA) of formula (IV)
with an alkylating agent in the presence of a proton acid and a solvent;·
ii. quenching the reaction mass of step (i) with water and inorganic halide;
iii. optionally separating the aqueous layer;
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 (Ill) 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 a proton
acid and a solvent. The alkylating agent is selected from the group consisting of
trialkyl orthoformate such as trimethylorthoformate thereof. The proton acid is
selected from the group consisting of alkyl or aryl sulfonic acid such as
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
naphthalenesulfonic acid. The solvent is selected from the group consisting of
esters of organic carboxylic acids such as formic acid methyl ester, formic acid
14
ethyl ester; esters of carbonic acid such as dimethyl carbonate, dipropyl
carbonate; nitriles such as acetonitrile, propionitrile, benzonitrile, malonitrile;
nitroalkanes such as nitromethane, nitroethane, nitropropane;. organic carboxylic
acids and esters thereof such as acetic acid, propionic acid, trifluoroacetic acid,
and esters thereof; ketones such as acetone, methyl ethyl . ketone, methyl
isobutyl ketone, acetophenone; halogenated alkanes such as dichloromethane,
chloroform, dichloroethane, carbon tetrachloride; halogenated alkenes such as
dichloroethylene, trichloroethylene; acid amides such · as formamide,
dimethylformamide, acetamide; ethers such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, aromatic hydrocarbons
· such as benzene, toluene, chlorobenzene, nitrobenzene; alkanes such as n- ·
hexane, heptane, alicyclic compounds such as cyclohexane; sulfolane; dimethyl
sulfoxide or mixture thereof.The reaction may be carried out at ooc to 30°C.
Most preferably at 15°C to 25°C.
The step ii) involves quenching the reaction mass of step (i) with water
and inorganic halide. The inorganic halide is selected from the group consisting
of sodium chloride, potassium chloride or mixture thereof. The reaction may be
carried out at -5°C to 15°C.
The step iii) involves separation of aqueous layer, optionally. When water
miscible solvent is utilized in step (1), aqueous solution is directly used for next
step without any layer separation.
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 aqueous
solution as obtained from step (ii) or (iii) with a base. he base is selected from the
group consisting of inorganic base, organic base or mixture thereof. The
inorganic base is selected fro~ the group of alkali carbonate such as sodium
carbonate, potassium carbonate, or alkali bicarbonate such as sodium
15
IPO DELHI 16:52
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
dialkyl anilines such as dimethyl. aniline or dimethylaminopyridine or N-methyl
morpholine or mixture thereof. Most perferably, aqueous ammonia. The reaction
may be carried out at ooc to 40°C. Most preferably at soc to 35°C.
The step v) involve~ condensation of 7 -amino 3-methoxymethyl-3-cephem
carboxylic acid (7 -AMCA) of formula (V) with 2-[2-aminothiazol-4-yl]:-2-synmethoxyimino
acetic acid-2-benzothiazolyl thioester of formula (Ill)· in the
presence of a base and a solvent to obtain cefpodoxime acid of formula (1). An
organic base is selected from the group consisting of triethylamine, pyridine, Nmethylpiperidine,
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,
dichloromethane, toluene, dioxane, isopropyl ether, dimethylformamide, NMethyl-
2-pyrrolidon, ethyl acetate, tetrahydrofuran, dimethylacetamide,
monglyme, diglyme, water and the like or mixture thereof. Most preferably
methanol or mixture of methanol and water. The reaction may be carried out at
ooc to 20°C. Most preferably at soc to 1S°C.
Following is the comparison of the result of Cefpodoxime acid prepared by
utilizing 7 -amino 3-methoxymethyl-3-cephem carboxylic acid (7 -AMCA) of
formula (V) which is prepared by the process of the present invention vis-a-vis
by the process disclosed in the prior arts.
16
IPO DEL.HI 28-04-2.016 /
Table-02
S.No Process Cefpodoxime acid Yield .HPLC Lactone
preparation (%) Purity Impurity
[utilizing 7 -AMCA of formula (V)] (%) (%)
1 Preparation by process 61-79 91-95 NA
disclosed in W000/68234
(Ranbaxy)
2 Preparation by process 47-56 89:-98 NA
disclosed in W02013041999 (assay)
(Dhanuka)
3 Preparation by utilizing AMCA 52-62 98.7-99 Not detected
prepared by present invention
The results clearly depict that when 7 -amino 3-methoxymethyl-3-cephem
carboxylic acid (7-AMCA) of formula (V) is prepared by using deacetyl-7-
aminocephalosporanic acid (D-7-ACA) of formula (IV), significantly improves the
purity and yield of the intermediate and also substantially reduces the lactone
impurity not only in the intermediate but also in the Cefpodoxime acid.
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 pharmaceutically 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.
17
IPO DELHI 28-04-2016
Examples:
EXAMPLE-1: Preparation of 7-amino 3-methoxymethyl-3-cephem carboxylic
acid (7 -AMCA) of formula (V)
100 g of deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV)
was suspended in 350 ml of dimethylcarbonate at ooc to 10°C under stirring. To
the solution, 110 g of trimethyl orthoformate was added at the same temperature.
200 g of methanesulfonic acid was slowly added in the reaction mass and stirred
the mass for 30-60 minutes. After the reaction completion, the reaction mass was
poured into the 20% brine solution. The aqueous layer was separated and its pH
was adjusted in the range of 3.0 to 3.5 with 20% aqueous ammonia solution. The
reaction mass was stirred for 30-60 minutes and the solid was filtered, washed
with water and finally with washed with 100 ml of methanol. 150 g of wet material
was obtained which was used for further step. Yield : 1.5 (w/w); HPLC purity:
'98.5%.
EXAMPLE-2: Preparation of 7-amino 3-methoxymethyl-3-cephem carboxylic
acid (7 -AMCA) of formula (V)
100 g of deacetyl-7 -aminocephalosporanic acid (D-7 -ACA) of formula (IV)
was suspended in 300 ml of dimethylcarbonate at ooc to 1 ooc under stirring. To
the solution, 100 g of trimethyl orthoformate was added at the same temperature.
200 g of methanesulfonic ·acid was slowly added in the reaction mass and stirred
the mass for 30-60 minutes. After the reaction completion, the reaction mass was
poured into the 20% brine solution. The aqueous layer was separated and its pH
was adjusted in the range of 3.0 to 3.5 with 20% aqueous ammonia solution. The
reaction mass was stirred for 30-60 minutes and the solid was filtered, washed
with water and finally with washed with 100 ml of methanol. It was dried to get 82
g of the title compound. Yield : 0.82 (w/w); HPLC purity: 98. %.
18
IPO DELHI z·S-04-201~ 1S:·52
EXAMPLE-3: Preparation of 7-amino 3-methoxymethyl-3-cephem carboxylic
acid (7-AMCA) of formula (V)
100 g of deacetyl-7 -aminocephalosporanic acid (D-7 -ACA) of formula (IV)
was suspended in 330 ml of dimethylcarbonate at ooc to 1 ooc under stirring. To
the solution, 90 g of trimethyl orthoformate was added at the same temperature.
150 g of methanesulfonic acid was slowly added in the reaction mass and stirred
the mass for 30-60 minutes. After the reaction completion, the reaction mass was
poured into th~ 20% brine solution. The aqueous layer was separated and its pH
was adjusted in the range of 3.-0 to 3.5 with 10% aqueous sodium bicarbonate
solution. The reaction mass was stirred for 30-60 minutes and the solid was
filte·red, washed with water and finally with washed with 100 ml of methanol. 140
g of wet material was obtained which was used for further step. Yield : 1.4 (w/w);
HPLC purity: 98.4%.
EXAMPLE-4: Preparation of 7 -amino 3-methoxymethyl-3-cephem carboxylic
acid (7 -AMCA) of formula (V)
1 00 g of deacetyl-7 -aminocephalosporanic acid (D-7 -ACA) of formula (IV)
•
was suspended in 300 ml of dichloromethane (MDC) at ooc to 1 ooc under
stirring. To the solution, 110 g of trimethyl orthoformate was added at the same
temperature. 200 g of methanesulfonic acid was slowly added in the reaction
mass and stirred the mass for 30-60 minutes. After the reaction completion, the
/
reaction mass was poured into the 20% brine solution. The aqueous layer was
separated and its pH was adjusted in the range of 3.0 to 3.5 with 10% aqueous
sodium bicarbonate solution. The reaction mass was stirred for 30-60 minutes
. and the solid was filtered, washed with water and finally with washed with 100 ml
of methanol. 125 g of wet material was obtained which was used for further step.
Yield : 1.25 (w/w); HPLC purity: 98.3%.
19
IPO DELHI 2S-a4-2016 16:52
EXAMPLE-S: Preparation of cefpodoxime acid of formula (I)
150 g of wet 3-methoxymethyl-7 -aminocephalosporanic acid (7 -AMCA)
which was obtained in Example-1 and 120 g of 2-[2-aminothiazol-4-yl]-2-synmethoxyimino
r~cetic acid-2-benzothiazolyl thioester (MAEM) were added in 450
ml of methanol at 20°C to 30°C. The reaction mixture was cooled to ooc to 15°C
and 40 g of triethylamine was added dropwise into it. The solution was stirred at
1 ooc 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 1 rc to 2.ooc for 3-
4 hrs. The solid was filtered, washed with water and finally with 100 ml of
acetone. It was dried to get 114 g of the title compound. Yield : 1:14 (w/w); HPLC
purity: 99.0%
EXAMPLE-6: Preparation of cefpodoxime acid of formula (I)
82 g of dry 3-methoxymethyl-7-aminocephalosporanic acid (7-AMCA)
which was obtained in Example-2 and 115 g of 2-[2-aminothiazol-4-yl]-2-synmethoxyimino
acetic acid-2-benzothiazolyl thioester (MAEM) were added in 450
ml of methanol and 65 ml of water at 20°C to 30°C. The reaction mixture was
cooled to ooc to 15°C and 40 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
20
I. P 0 DEL HI. 2 & -· 0 4 -· 2 0 l 6. , 6 · r ·") ..&. . . •' • _, '-
IPO
stirred at 17°0 to 20°0 for 3-4 hrs. The solid was filtered, washed with water and
finally with 100 ml of acetone. It was dried to get 105 g of the title compound.
Yield : 1.05 (w/w); HPLO purity: 98.9%
EXAMPLE-7: Preparation of cefpodoxime acid of formula (I)
125 g of wet 3-methoxymethyl-7 -aminocephalosporanic acid (7 -AMOA)
which was obtained in Example-4 and 110 g of 2-[2-aminothiazol-4-yl]-2-synmethoxyimino
acetic acid-2-benzothiazolyl thioester (MAEM) were added in 450
ml of methanol at 20°0 to 30°0. The reaction mixture was cooled to ooo to 15°0
and 40 g of triethylamine was added dropwise into it. The solution was stirred at
10°0 to 18°0 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 HOI at 2.0-2.1 and stirred at 1 ro to 20°0 for 3-
4 hrs. The solid was filtered, washed with water and finally with 100 ml of
acetone. It was dried to get 95 g of the title compound. Yield : 0.90 (w/w); HPLO
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 -AMOA) of formula (V) as well as of cefpodoxime
acid of formula (I).
21
DElHI 28-04-2016 16 :. S2
ii. The process of the present invention avoids excess usages of reagent(s) and
organic solvent(s), thereby promoting green chemistry and ensuring a cleaner
surrounding by putting less load on environment.
iii. The process of the present invention avoids the use of reagent like BF3 which
is harmful to the environment and is very hazardous in nature.
iv. This process of replacing BF3 or its complex such as dimethoxycarbeniumtetrafluoroborate
with methanesulfonic acid has substantial advantages in
terms of cost on a manufacturing scale.
v. 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:
1. A process for the preparation of 7 -amino 3-methoxymethyl-3-cephem carboxylic
acid (7-AMCA) of formula (V),
Formula (V)
which comprises the steps of:
i. reacting deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula {1\() with
an alkylating agent in the presence of a proton acid and a solvent;
ii. quenching the reaction mass of step (i) with water and inorganic halide;
iii. optionally separating the aqueous layer; 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.
2. The process according to claim 1, wherein the alkylating agent in step (i) is
selected from the group consisting of trialkyl orthoformate such as trimethyl
orthoformate thereof.
'
3. The process according to claim 1, wherein the proton 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, naphthalenesulfonic acid.
23
IPO DELHI 28-04-2016 16:52
4. The process according to claim 1, wherein the solvent in step (i) is selected from
the group consisting of esters of organic carboxylic acids such as formic acid
methyl ester, formic acid ethyl ester; esters of carbonic acid such as dimethyl
carbonate, dipropyl carbonate; nitriles such as acetonitrile, propionitrile,
benzonitrile, malonitrile; nitroalkanes such as nitromethane, nitroethane,
nitropropane; organic carboxylic acids and esters thereof such as acetic acid,
propionic acid, trifluoroacetic acid, and esters ~hereof; ketones such as acetone, ·
methyl ethyl ketone, methyl isobutyl ketone, acetophenone; halogenated alkanes
such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride;
halogenated alkenes such as dichloroethylene, trichloroethylene; acid amides
such as formamide, dimethylformamide, acetamide; ethers such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether,
aromatic hydrocarbons such as _benzene, toluene, chlorobenzene, nitrobenzene;
alkanes such as n-hexane, heptane, alicyclic compounds such as cyclohexane;
sulfolane; dimethyl sulfoxide or mixture thereof.
5. The process according to claim 1, wherein the inorganic halide in step (ii) is
selected from the group consisting of sodium chloride, potassium chloride or
mixture thereof.
6. The process according to claim 1, wherein the base in step (iv) 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.
7. The process according to claim 1, further comprising step of reacting 7 -amino 3-
methoxymethyl-3-cephem carboxylic acid (7 -AMCA) of formula (V) with 2-[2-
24
IPO DELHI 28-04-2016
aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-benzothiazolyl thioester of
formula (Ill) in the presence of a base and a solvent to obtain cefpodoxime acid
of formula (I).
8. The process according to claim 7, wherein the organic base is selected from the
group consisting of triethylamine, pyridine, N-methylpiperidine, 1,8-
diazabicycloundecene, 4-dimethylaminopyridine or mixtures thereof.
9. The process according to claim 7, wherein the solvent is selected from the group
consisting of methanol, ethanol, isopropanol, acetone, acetonitrile,
dichloromethane, toluene, dioxane, isopropyl ether, dimethylformamide; NMethyl-
2-pyrrolidon, ethyl acetate, tetrahydrofuran, dimethylacetamide,
monglyme, diglyme, water or mixture thereof.
10. A process for the preparation of cefpodoxime acid of formula (I),
Formula (I)
which comprises the steps of:
i. reacting deacetyl-7-aminocephalosporanic acid (D-7-ACA) of formula (IV) with
an alkylating agent in the presence of a proton acid and a solvent;
ii. quenching the reaction mass of step (i) with water and inorganic halide;
25
IPO DELHI 2:&-84-2016
~----------------------------------------------------------------------------
iii. optionally separating the aqueous layer;
iv. precipitating ?-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 ?-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 (Ill) in the presence of a base and a solvent
to obtain cefpodoxime acid of formula (I).