FOR THE PREPARATION OF CEFTAROLINE FOSAMIL AND ITS
INTERMEDIATES
Field of the Invention
The present invention provides a process for the preparation of ceftaroline fosamil and its
intermediates. The present invention also provides a process for the preparation of ceftaroline
fosamil propionate monohydrate and ceftaroline fosamil acetate monohydrate.
Background of the Invention
Ceftaroline fosamil acetate monohydrate chemically is (6,7)-7-((2Z)-2-(ethoxyimino)-2-
thiazol-2-yl] sulfanyl} -8-0x0-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylate monoacetate
monohydrate of Formula I.
f cH3
Formula I
Ceftaroline fosamil acetate monohydrate is a phosphate prodrug of ceftaroline of
Formula I1 and is indicated for the treatment of acute bacterial skin and skin structure infections
and community-acquired bacterial pneumonia.
rcH3
0- A0
Formula I1
JP Patent No. 3927262 B2 provides a process for the pr:.paration of ceftaroline, wherein
7-amino-3-[4-(1-methylpyridinium-4-yl)thiazol-2-yl]thio-3-cephem-4-carboxylatise treated
with 2-(5-amino-1,2,4-thiadiazo1-3-y1)-2(Z)-ethoxyiminoacety1 chloride hydrochloride. The
product is isolated by chromatography and lyophilized to provide lyophilized ceftaroline.
2
0 U.S. Patent No. 6,417,175 provides a process for the preparation of ceftaroline fosamil,
wherein 7 P-amino-3-[4-(1 -methyl-4-pyridinio)-2-thiazolylthio]-3-cephem-4-c~boxylate
hydrochloride is treated with 2-(5-dichlorophosphorylamino- 1,2,4-thiadiazol-3-y1)-2(Z)-
ethoxyiminoacetyl chloride to obtain a mixture containing ceftaroline fosarnil. The mixture is
purified by column chromatography and the fractions containing the desired compound are
concentrated under reduced pressure. The concentrate is lyophilized to obtain lyophilized
ceftaroline fosamil.
U.S. Patent No. 6,906,055 provides processes for the preparation of disodium salt of
ceftaroline fosarnil, ceftaroline fosamil, ceftaroline fosamil propionate and ceftaroline fosamil
acetate. The processes mentioned therein involve the use of chromatography and
ultrasonication.
U.S. Patent No. 6,906,055 also provides a process for the preparation of 2-(5-
dichlorophosphorylamino- 1,2,4-thiadiazol-3-y1)-2(Z)-ethoxyiminoacetyl chloride from 2-(5-
amino-1,2,4-thiadiazo1-3-y1)-2(Z)-ethoxyiminoacetiacc id, wherein the acid chloride is isolated.
Acid chlorides are unstable and difficult to handle at industrial scale.
U.S. Patent No. 6,906,055 also provides a process for the preparation of 7P-amino-3-[4-
(1 -methyl-4-pyridinio)-2-thiazolylthio]-3-cephem-4-carboxylate dihydrochloride from
benzhydryl 7P-[(phenylacetyl)amino]-3-[4-(1 -methyl-4-pyridinio)-2-thiazolylthio]-3-cephem-4-
carboxylate iodide in low yield using isobutyl alcohol. The removal of high boiling isobutyl
alcohol makes the product susceptible to degradation and decreases the yield of the product.
PCT Publication No. WO 201 11035305 provides compositions of ceftaroline fosamil
comprising from about 0.05% to about 10% of impurities including ceftaroline, ring opened
ceftaroline, diphosphoric type ceftaroline, dimer of ceftaroline acetate, delta 2-type ceftaroline
acetate, amide type impurity, desmethyl type ceftaroline acetate and acetyl type ceftaroline
acetate.
The prior art processes for the preparation of ceftaroline fosamil or its salt or its solvate
involve the application of tedious chromatography, ultrasonication and lyophilization
techniques. Further, the prior art processes for the preparation of ceftaroline fosamil
intermediates, 2-(5-dichlorophosphorylamino- 1,2,4-thiadiazol-3-y1)-2(Z)-ethoxyiminoacetyl
chloride and 7P-amino-3-[4-(1 -methyl-4-pyridinio)-2-thiazolylthio]-3-cephem-4-carboxylate
dihydrochloride, are not suitable at industrial scale.
The present invent6rs have developed simple, safe, efficient, economical, industrially
feasible processes that provide ceftaroline fosamil or its salt or its solvate and its intermediates
in good yield and purity.
Summary of the Invention
The present invention provides a process for the preparation of ceftaroline fosamil and its
intermediates. The present invention also provides a process for the preparation of ceftaroline
fosamil propionate monohydrate and ceftaroline fosamil acetate monohydrate.
Detailed Description of the Invention
A first aspect of the present invention provides a process for the preparation of a
compound of Formula I11
Formula I11
wherein the process comprises:
a) treating a compound of Formula IV
I -
Formula IV
with phosphorus chloride in the presence of a base,
b) adding a low boiling solvent; and
c) adding hydrochloric acid to the reaction mass of step b) to obtain the compound of Formula
111.
The compound of Formula I11 prepared according to above process may further be
converted to ceftaroline fosamil or its salt or its solvate.
A second aspect of the present invention provides a process for the preparation of a
compound of Formula I11
Formula I11
wherein the process comprises:
a) treating a compound of Formula IV
Formula IV
with phosphorus chloride in the presence of a base,
b) adding methanol; and
c) adding hydrochloric acid to the reaction mass of step b) to obtain the compound of Formula
111.
The compound of Formula I11 prepared according to above process may further be
converted to cefiaroline fosamil or its salt or its solvate.
The compound of Formula IV may be prepared by any method provided in the art, for
example, the process described in U.S. Patent No. 6,906,055. The compound of Formula IV
may be treated with phosphorus chloride in the presence of a base in a solvent. The compound
of Formula IV is treated with a mixture of a base and phosphorus chloride in a solvent. The
mixture of a base and phosphorus chloride in a solvent may be stirred from about 5 minutes to
about 2 hours at about O°C to about 1 5 " p~ri or to the treatment with the compound of Formula
IV. A base may be, for example, pyridine or dimethylamine. Phosphorus chloride may be, for -
example, phosphorus pentachloride. A solvent may be, for example, dichloromethane,
dichloroethane or a mixture thereof. The compound of Formula IV may be treated with
phosphorus chloride in the presence of a base at about 0°C to about 15OC and the reaction
@ mixture may be stirred from about 30 minutes to about 4 hours. A low boiling solvent may be
added at about 0°C to about -30°C. The low boiling solvent may be added in one lot or in
portions. The addition of low boiling solvent may be followed by stirring from about 0.5 hour to
about 4 hours at about 10°C to about 50°C. Hydrochloric acid may be added at about 10°C to
about 50°C. A nitrile solvent, for example, acetonitrile may be added along with the addition of
hydrochloric acid. The reaction mass may be stirred from about 0.5 hour to about 5 hours at
about 20°C to about 50°C. The compound of Formula IS1 may be isolated from the mixture by
the methods including concentration, distillation, decantation, filtration, evaporation,
centrifugation or a combination thereof and may further be dried.
The term "low boiling solvent" as used herein, refers to a solvent having a boiling point
of 85°C or less. A low boiling solvent may be, for example, methanol, ethanol, acetone, ethyl
acetate, methyl tert-butyl ether, 2-propanol. and tetrahydrofuran.
The process for the preparation of the compound of Formula 111 of the present invention
provides the compound of Formula 111 in 81.7% yield. On the other hand, the yield of the
compound of Formula IS1 obtained by the prior art process, reference example 15 of U.S. Patent
No. 6,906,055, is 63%.
A third aspect of the present invention provides a process for the preparation of
ceftaroline fosamil of Formula Ia
rcH3
Formula Ia
or its salt or its solvate, wherein the process comprises:
a) reacting a compound of Formula V
Formula V
with phosphorus chloride in one or more organic solvents,
b) optionally, adding water and separating the organic layer,
c) concentrating the resulting mass of step a) or the separated organic layer of step b) to obtain a
residue,
d) adding a water miscible solvent to the residue of step c) to obtain a solution; and
e) treating the solution of step d) with a compound of Formula I11
Formula I11
to obtain the ceftaroline fosamil of Formula Ia.
A fourth aspect of the present invention provides a process for the preparation of
ceftaroline fosamil propionate monohydrate of Formula Ib
rcH3
0
Formula Ib
wherein the process comprises:
a) reacting a compound of Formula V
H~N-;~U;:-$~~ S-N
0
Formula V
with phosphorus chloride in one or more organic solvents,
b) optionally, adding water and separating the organic layer,
c) concentrating the resulting mass of step a) or the separated organic layer of step b) to obtain a
residue,
d) adding a water miscible solvent to the residue of step c) to obtain a solution,
e) treating the solution of step d) with a compound of Formula 111;
Formula I11
and
f) treating the resulting mass of step e) with propionic acid or a mixture of propionic acid and
water to obtain the ceftaroline fosamil propionate monohydrate of Formula Ib.
A fifth aspect of the present invention provides a process for the preparation of
ceftaroline fosamil acetate monohydrate of Formula I
/CH3
N'O
H oo4 .bp, / ~ SH-N~ N ~ N0 e J A+ s \ / +'cH3 R N ' s -N
0
Formula I
wherein the process comprises:
a) reacting a compound of Formula V
Formula V
with phosphorus chloride in one or more organic solvents,
b) optionally, adding water and separating the organic layer,
c) concentrating the resulting mass of step a) or the separated organic layer of step b) to obtain a
residue,
d) adding a water miscible solvent to the residue of step c) to obtain a solution,
e) treating the solution of step d) with a compound of Formula 111
Formula 111
f ) treating the resulting mass of step e) with propionic acid or a mixture of propionic acid and
water to obtain cefiaroline fosamil propionate monohydrate of Formula Ib;
rcH3
Formula Ib
and
g) converting the cefiaroline fosamil propionate monohydrate of Formula Ib into the cefiaroline
fosamil acetate monohydrate of Formula I.
A sixth aspect of the present invention provides a process for the preparation of
cefiaroline fosamil acetate monohydrate of Formula I
rCH3
N,O
Formula I
@ wherein the process comprises converting ceftaroline fosamil propionate monohydrate of
Formula Ib
rcH3
Formula Ib
into ceftaroline fosamil acetate monohydrate of Formula I.
The compound of Formula V may be prepared by any method provided in the art, for
example, the process described in Chinese Publication No. CN 101987837. The compound of
Formula V may be treated with phosphorus chloride in one or more organic solvents at about
0°C to about 15OC for about 0.5 hour to about 4 hours. The phosphorus chloride may be mixed
with one or more organic solvents prior to the treatment with the compound of Formula V.
Phosphorus chloride may be, for example, phosphorus pentachloride. An organic solvent may
be a mixture of a hydrocarbon solvent and an ester solvent. A hydrocarbon solvent may be, for
example, toluene. An ester solvent may be, for example, ethyl acetate. The reaction mass may
be treated with an aqueous solution of sodium chloride and stirred from about 5 minutes to about
30 minutes at about 5OC to about 30°C. The reaction mass may be cooled to about -5°C to about
-30°C prior to the treatment with aqueous solution of sodium chloride. The organic layer may
be separated and concentrated under reduced pressure at about 35OC to about 60°C to obtain a
residue.
A water miscible solvent is added to the residue to obtain a solution. The solution
obtained after adding a water miscible solvent to the residue is treated with the compound of
Formula I11 in the presence of an alkali metal salt. A water miscible solvent may be, for
example, tetrahydrofuran. The solution may be treated with the compound of Formula 111 at
about O°C to about 15OC. The solution may be added to a mixture of the compound of Formula
111. and water or a mixture of the compound of Formula 111 and water may be added to the
solution. The alkali metal salt may be used as such or in the form of aqueous solution. The
alkali metal salt may be, for example, sodium acetate, potassium acetate or a mixture thereof.
The pH of the mixture may be adjusted from about 4 to about 5 and the mixture may be stirred
from about 1 hour to about 6 hours at about O°C to about 30°C. The mixture obtained may
a optionally be treated with a water immiscible solvent, for example, ethyl acetate and aqueous
layer may be separated. The pH of the aqueous layer may be adjusted from about 0.5 to about
2.5 with an inorganic acid at about 0°C to about 30°C and the reaction mixture may be stirred
from about 15 minutes to about 2 hours at about 0°C to about 30°C. An inorganic acid may be,
for example, hydrochloric acid or sulfuric acid. The resulting mass containing the compound of
Formula Ia or its salt may be isolated as a residue from the mixture by the methods including
concentration, distillation, decantation, filtration, evaporation, centrifugation or a combination
thereof and may be used as such in the next step.
The residue is treated with propionic acid or a mixture of propionic acid and water. The
residue may optionally be treated with an alkali metal salt at about 5OC to about 30°C prior to the
treatment with propionic acid or a mixture of propionic acid and water. The mixture obtained
after adding propionic acid or a mixture of propionic acid and water may be stirred from about 1
minute to about 30 minutes at pH from about 0.2 to about 4. Seed crystals of ceftaroline fosamil
propionate monohydrate may be added to the mixture and the mixture may further be stirred
from about 2 hours to about 20 hours at about 5°C to about 30°C. The seed of ceftaroline
fosamil propionate monohydrate may be prepared by any method provided in the art, for
example, the process described in U.S. Patent No. 6,906,055. The pH of the mixture may be
adjusted to about 0.2 to about 4 with an inorganic acid, for example, sulfuric acid, prior to
seeding. The compound of Formula Ib, having HPLC purity of 91.37% or more, may be
isolated from the mixture by the methods including concentration, distillation, decantation,
filtration, evaporation, centrifugation or a combination thereof and may further be dried.
The compound of Formula Ib is treated with acetic acid or a mixture of acetic acid and
water to obtain ceftaroline fosamil acetate monohydrate of Formula I. The compound of
Formula Ib may optionally be treated with an alkali metal salt at about 5°C to about 30°C prior
to the treatment with acetic acid or a mixture of acetic acid and water. Seed crystals of
ceftaroline fosamil acetate monohydrate may be added to the mixture and the mixture may be
stirred from about 15 minutes to about 10 hours at about 5°C to about 30°C. The seed of
ceftaroline fosamil acetate monohydrate may be prepared by any method provided in the art, for
exampie, the process described in U.S. Patent No. 6,906,055. The mixture may optionally be
treated with an inorganic acid, for example, sulfuric acid, prior to seeding. The compound of
Formula I, having HPLC purity of 94.17% or more, may be isolated from the mixture by the
methods including concentratibn, distillation, decantation, filtration, evaporation, centrifugation
or a combination thereof and may further be dried.
The process for the preparation of ceftaroline fosamil propionate monohydrate provided
in the present invention avoids the tedious chromatography, ultrasonication and lyophilization
11
techniques and provides ceftaroline fosamil propionate monohydrate in good yield and purity.
The ceftaroline fosamil propionate monohydrate prepared according to the process of the present
invention can be converted to ceftaroline fosamil acetate monohydrate having good yield and
purity.
The term "residue" as used herein, refers to a concentrated mass from which a solution
can be prepared by using a water miscible solvent.
The term "about", as used herein, when used along values assigned to certain
measurements and parameters means a variation of 10% from such values, or in case of a range
of values, means a 10% variation from both the lower and upper limits of such ranges.
While the present invention has been described in terms of its specific embodiments,
certain modifications and equivalents will be apparent to those skilled in the art and are intended
to be included within the scope of the present invention.
EXAMPLES
Example 1 : Preparation of 7P-amino-3-r4-(1 -methyl-4-pyridinio)-2-thiazolylthiol-3-cephem-4-
carboxylate dihydrochloride (Formula 111)
Phosphorus pentachloride (7.6 g, 364 mmoles) was suspended in dichloromethane (50
mL) and the mixture was cooled to 0°C to 5°C. Pyridine (2.7 g, 364 mmoles) was added slowly
to the mixture and it was stirred for 30 minutes. Benzhydral 7P-[(phenylacetyl)amino]-3-[4-(1-
methyl-4-pyridinio)-2-thiazolylthio]-3-cephem-4-carboxylatei odide (Formula IV, 10 g, 122
mmoles) was added to the mixture and it was stirred for 1 hour at O°C to 5OC. The reaction mass
was cooled to -20°C and methanol (50 mL) was added to the reaction mass in one lot. The
temperature of the reaction mass was raised to 25OC to 30°C and it was stirred for 1.5 hours to 2
hours. Acetonitrile (70 mL) and hydrochloric acid (35%, 30 mL) were added to the resulting
mass and it was stirred for 2 hours at 40°C to 45°C. The crystalline white solid precipitate
obtained was cooled to 30°C to 35OC and the solid was filtered. The wet solid was suspended in
methanol (25 mL) and the mixture was stirred for 1 hour at 20°C to 25'C. The solid was
filtered, washed with methanol (10 mL) and dried in air oven at 40°C to 45OC.
Yield = 4.8 g (81.7%)
HPLC purity = > 98.5%
@ Example 2: Preparation of ceftaroline fosamil propionate monohydrate (Formula Ib)
Step a): Preparation of 2-(5-dichlorophosphorylamino-l,2,4-thiadiazol-3-yl)-2-(2)-
ethoxyiminoacetyl chloride
Phosphorus pentachloride (36 g, 172 mmoles) was added to a mixture of toluene (300
mL) and ethyl acetate (30 mL). The mixture was cooled to O°C to 5OC and 2-(5-amino-1,2,4-
thiadiazol-3-y1)-2-(Z)-ethoxyimino acetic acid (Formula V, 15 g, 69 mmoles) was added. The
reaction mixture was stirred for 1 hour at O°C to 5OC and then cooled to -15OC to -20°C. An
aqueous solution of sodium chloride (lo%, 300 mL) was added to the reaction mass in 15
minutes to 20 minutes and stirred for 15 minutes at 10°C to 15OC. The organic layer was
separated and washed with aqueous sodium chloride (lo%, 300 mL). The organic layer was
completely concentrated under reduced pressure at 50°C to 55OC. Toluene (2 x 100 mL) was
added to the residue and solvent was distilled out completely under reduced pressure. The
residue obtained was dissolved in tetrahydrofuran (1 00 mL) and used as such for next step.
Step b): Preparation of 3-[4-(1 -methyl-4-pyridinio~-2-thiazolylthiol-7~hosphonoamino-
1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamidol-3-cephem-4-carboxyla(tFeo rmula Ia)
7P-Amino-3-[4-(1 -methyl-4-pyridinio)-2-thiazolylthio]-3-cephem-4-carboxylate
dihydroch!oride (Formula 111, 20 g, 41.7 mmoles) was added to water (400 mL) at O°C to 5OC
and a solution of 2-(5-dichlorophosphorylamino- 1,2,4-thiadiazol-3-y1)-2-(Z)-ethoxyiminoacetyl
chloride (prepared according to Step a) in tetrahydrofuran was added. A solution of sodium
acetate (1 11 g, 840 mmoles) in water (200 mL) was added to the resulting mixture in 20 minutes
to 25 minutes at 5OC to 10°C and pH was adjusted to about 4.48. The reaction mixture was
stirred for 3 hours at 5OC to 15OC. Ethyl acetate (200 mL) was added to the reaction mass and it
was stirred for 10 minutes. The aqueous layer was separated and pH of the aqueous layer was
adjusted from about 2.0 to about 2.2 with 6N hydrochloric acid at 10°C to 15OC. The aqueous
layer was degassed under reduced pressure to remove residual solvent. Eno-anticromos carbon
(2 g), sodium metabisulfite (0.2 g), ethylenediaminetetraacetic acid (0.2 g) were added to
aqueous layer and it was stirred for 20 minutes to 25 minutes at 10°C to 15OC. The resulting
mixture was filtered through hyflo bed and hyflo bed was washed with water (100 mL). The
filtrate was cooled to 5OC to 10°C and pH was adjusted from about 0.6 to about 0.7 with 6N
hydrochloric acid. The mixture was stirred at low round per minute for 1 hour at O°C to 5OC.
The solid was filtered and washed with water (100 mL). The wet solid was used as such in the
next step.
Step c): Preparation of ceftaroline fosamil propionate monohydrate (Formula Ib)
The wet solid (20 g, 29.2 mmoles) obtained according to step b), was added slowly to a
solution of sodium acetate (10 g, 73.5 mmoles) and D-mannitol (5 g, 27.1 mmoles) in water (40
mL). The mixture was stirred for 15 minutes to 20 minutes at 20°C to 25OC and pH was
adjusted to about 3.5. Propionic acid (120 mL) was added to the mixture and it was stirred for 5
minutes. Sulfuric acid (2M, 30 mL) was added to the reaction mixture in 10 minutes to 15
minutes at 20°C to 25OC and the pH of the mixture was adjusted to about 0.8. Seed crystals of
ceftaroline fosamil propionate monohydrate (0.2 g) were added to the mixture and the mixture
was stirred for 12 hours at 20°C to 25OC. The solid was filtered, washed with a mixture of water
and propionic acid (1:1, 2 x 50 mL) and water (2 x 50 mL). The solid was dried under vacuum
at 40°C to 45OC.
Yield = 18 g (56%)
HPLC Purity = 91.37%
Example 3: Preparation of ceftaroline fosamil acetate monohydrate (Formula I)
Ceftaroline fosamil propionate monohydrate (Formula Ib, 10 g, 128 mmoles) was
dissolved in a mixture of sodium acetate (4.5 g, 330 mmoles) and D-mannitol (2.5 g, 136
mmoles) in water (35 mL) at 20°C to 25OC. Acetic acid (50 mL) and eno-anticromos carbon
(0.5 g) were added to the mixture and it was stirred for 30 minutes. The resulting mixture was
filtered through hyflo bed and hyflo bed was washed with a mixture of acetic acid and water (20
mL, 1 : 1). The filtrate was passed through 0.45 p filter. Sulfuric acid (2M, 13 mL) was added to
the filtrate slowly and the mixture was stirred for 5 hours with addition of seed crystals of
ceftaroline fosamil acetate monohydrate (0.1 g) at 25OC to 30°C. The slurry obtained was
filtered and washed with a mixture of acetic acid and water (1: 1, 2 x 30 mL) and water (2 x 30
mL). The solid was washed with ethanol (10 mL) and dried under vacuum at 40°C to 45' for 12
hours.
Yield = 6.3 g (64%)
HPLC Purity = 94.17%

WE CLAIM:
1. A process for the preparation of a compound of Formula 111
Formula I11
wherein the process comprises:
a) treating a compound of Formula IV
Formula IV
with phosphorus chloride in the presence of a base,
b) adding a low boiling solvent; and
c) adding hydrochloric acid to the reaction mass of step b) to obtain the compound of Formula
111.
2. The process according to claim 1, wherein the low boiling solvent is selected from methanol,
ethanol, acetone, ctliyl acetate. methyl tert-butyl ether, 2-propanol, and tetrahydrof~~ran;
phosphorus chloride is phosphorus pentachloride; and the base is selected from pyridine or
dimethylamine.
3. The process according to cla& 1, wherein the compound of Formula IV is treated with a
mixture of a base and phosphorus chloride in a solvent selected from dichloromethane,
dichloroethane or a mixture thereof.
4. A process for the preparation of ceftaroline fosarnil of Formula la
rCH3
N'O
0 - 4 0
Formula Ia
or its salt or its solvate, wherein the process comprises:
a) reacting a compound of Formula V
~~~-;i"fi~~ S-N
0
Formala V
with phosphorus chloride in one or more organic solvents:
b) optionally, adding water and separating the organic layer,
c) concentrating the resulting mass of step a) or the separated organic layer of step b) to obtain a
residue,
d) adding a water miscible solvent to the residue of step c) to obtain a solution; and
e) treating the solution of step d) with a compound of Formula I11
Formula 111
to obtain the ceftaroline fosamil of Formula Ia.
0 5. A process for the preparation of ceftaroline fosarnil propionate monohydrate of Formula Ib
Formula Ib
wherein the process comprises:
a) reacting a compound of Formula V
H ~ N - ~ . ) + ~ ~
S-N
0
Formula V
with phosphorus chloride in one or more organic solvents,
b) optionally, adding water and separating the organic layer,
c) concentrating the resulting mass of step a) or the separated organic layer of step b) to obtain a
residue,
d) adding a water miscible solvent to the residue of step c) to obtain a solution,
e) treating the solution of step d) with a compound of Formula 111;
Formula I11
and
f) treating the resulting mass of step e) with propionic acid or a mixture of propionic acid and
water to obtain the ceftaroline fosamil propionate monohydrate of Formula Ib.
6. A process for the preparation of ceftaroline fosarnil acetate monohydrate of Formula I
Formula I
wherein the process comprises:
a) reacting a compound of Formula V
"'"-;i*
S-N
0
Formula V
with phosphorus chloride in one or more organic solvents,
b) optionally, adding water and separating the organic layer,
c) concentrating the resulting mass of step a) or the separated organic layer of step b) to obtain a
residue,
d) adding a water miscible solvent to the residue of step c) to obtain a solution,
e) treating the solution of step d) with a compound of Formula 111
Formula I11
f) treating the resulting mass of step e) with propionic acid or a mixture of propionic acid and
water to obtain ceftaroline fosamil propionate monohydrate of Formula 4b;
Formula Ib
and,
g) converting the ceftaroline fosamil propionate monohydrate of Formula Ib into the cefiaroline
fosamil acetate monohydrate of Formula I.
7. The process according to claims 4, 5 or 6, wherein phosphorus chloride is phosphorus
pentachloride and the organic solvent is a mixture of a hydrocarbon solvent and an ester solvent.
8. The process according to claims 4, 5 or 6, wherein the water miscible solvent is
tetrahydrofuran.
9. A process for the preparation of ceftaroline fosamil acetate monohydrate of Formula I
rcH3
N'O
CH3COOH H20
0 -
Formula I
wherein the process comprises converting ceftaroline fosamil propionate monohydrate of
Formula Ib
Formula Ib
into ceftaroline fosamil acetate monohydrate of Formula I.
10. The process according to claim 9, wherein the compound of Formula Ib is treated with acetic
acid or a mixture of acetic acid and water to obtain ceftaroline fosamil acetate monohydrate of
Formula I.