PREPARATION OF ANHYDROUS AMINO THIAZOLE DERIVATIVE
INTRODUCTION
Aspects of the present application relates to process for the preparation of
anhydrous (2Z)-[(acetyloxy)imino](2-amino-I ,3-thiazol-4-yl)ethanoic acid represented
by the Formula I.
FORMULA I
Thiazole derivative of Formula I is an intermediate for cefdinir represented
by the Formula II.
FORMULA II
The drug compound having the adopted name "Cefdinir" has a chemical
name (6Rl7R)-7-[[(2Z)-(2-amino-4-thiazolyl)(hydroxyimino)acetyl]amino]-3-ethenyl
-8-0x0-5-thia-I -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Cefdinir (marketed in US market as OMNICEFO) is an extended-spectrum,
semisynthetic cephalosporin for oral administration to treat or prevent infections
that are proven or strongly suspected to be caused by susceptible bacteria.
EP 214462 A2 discloses thiazole derivative of Formula I or its reactive
derivative.
Canadian patent, CA 1,340,604 C, discloses a process for the preparation
of hydrated thiazole derivative of Formula IV from sodium HATA dihydrate of
Formula Ill.
FORMULA Ill FORMULA IV
US patent, US 6,878,827 B2, generically claims a process for preparation
of thiazole derivative in anhydrous form (Formula I), comprising treating hydrated
thiazole derivative of Formula IV in a ketone or acetonitrile.
The prior art methods for the preparation of anhydrous thiazole derivative of
Formula I either employ expensive solvents or have poor recovery of solvents. In
addition, prior art methods are associated with formation of varying amounts of
impurities which give the product in low purity, rendering such methods less
efficient.
There still remains a need to provide an efficient and improved process for
the preparation of highly pure anhydrous thiazole derivative of Formula I which is
simple, cost-effective, commercially viable, sustainable, and eco-friendly.
The main object of the present application is to provide a process for
preparation of anhydrous thiazole derivative of Formula I, which is simple,
economical, user-friendly and commercially viable.
Yet, another objective of the present application is to provide process for
the preparation of anhydrous thiazole derivative of Formula I with high purity which
can be advantageously used in the preparation of cefdinir with high purity and
substantially free of impurities.
SUMMARY
In an aspect, the present application provides a process for the preparation
of anhydrous thiazole derivative of Formula I,
A FORMULA I
H2N N-0
the embodiments comprising one or more of the following steps, individually or in
the sequence recited:
i) suspending hydrated thiazole derivative of Formula IV,
H2N A
N-0
. 2 ~ ~ 0FO RMULA IV
k ~ ~ 3
0
in suitable solvent;
ii) optionally, refluxing suspension of step i);
iii) optionally, cooling suspension of step ii);
iv) filtering resulting suspension;
v) washing solid, as obtained from step iv), with suitable solvent;
vi) drying solid, as obtained from step v), to obtain anhydrous thiazole
derivative of Formula I; and
vii) optionally, using anhydrous thiazole derivative of Formula I in the
preparation of cefdinir of Formula II.
DETAILED DESCRIPTION
All temperatures are in degrees Celsius ("C.) unless specified otherwise. All
measurements made are at about 25°C. and about atmospheric pressure, and all
percentages and ratios used herein are by weight of the total composition, unless
otherwise designated.
As used herein, "comprising1' means the elements recited, or their
equivalent in structure or function, plus any other element or elements that are not
recited. The terms "having" and "including" are also to be construed in the same
manner. All ranges recited herein include the endpoints, including those that recite
a range "between" two values.
The term "anhydrous" should be understood to mean that the products
obtainable in accordance with the process of present application have less than
1 .O% moisture content.
In an aspect, the present application provides a process for the preparation
of anhydrous thiazole derivative of Formula I,
FORMULA I
the embodiments comprising one or more of the following steps, individually or in
the sequence recited:
i) suspending hydrated thiazole derivative of Formula IV,
0
H2N . 2 ~ ~ 0FO RMULAIV
N-0
in suitable solvent;
ii) optionally, refluxing suspension of step i);
iii) optionally, cooling suspension of step ii);
iv) filtering resulting suspension;
v) washing solid, as obtained from step iv), with suitable solvent;
vi) drying solid, as obtained from step v), to obtain anhydrous thiazole
derivative of Formula I; and
vii) optionally, using anhydrous thiazole derivative of Formula I in the
preparation of cefdinir of Formula II.
Hydrated thiazole derivative of Formula IV may be prepared using any
processes known in the art.
Suitable solvents of step i) and step v) include, but are not limited to: an
alcohol, e.g., methanol, ethanol, isopropanol, n-propanol, n-butanol, 2-butanol,
and the like; a halogenated hydrocarbon, e.g., dichloromethane, ethylene
dichloride, chloroform, and the like; an ether, e.g., diethyl ether, diisopropyl ether,
methyl t-butyl ether, tetrahydrofuran, dioxane, and the like; and any mixtures
thereof. Preferably, suitable solvents in step i) are methanol, isopropanol,
tetrahydrofuran, dichloromethane, and mixtures thereof.
Suitable times for refluxing the suspension of the step i) depend on the
temperature and other conditions, and may be generally less than about 10 hours,
less than about 5 hours, or less than about 2 hours, or less than about 1 hour, or
any other suitable times. Longer times are also suitable.
Preferably, washing of solid in step v) is done with chilled solvent.
Drying may be carried out at temperatures less than about 100°C., or less
than about 60°C., or less than about 40°C., or any other suitable temperatures, at
atmospheric pressure or under reduced pressure, and in the presence or absence
of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may
be carried out for any desired time periods to achieve the desired quality of the
product, such as, for example, about 1 to about 15 hours, or longer. Further,
drying may be suitably carried out using techniques including tray drying, vacuum
drying, air drying, fluidized bed drying, spin flash drying, flash drying, spray drying,
thin film drying, freeze drying, and the like, at atmospheric pressure or under
reduced pressure.
Optionally, anhydrous thiazole derivative of Formula I is used in the
preparation of cefdinir of Formula II.
-. .
COOH
Following is the comparison chart of the result of intermediate as prepared
by the process disclosed in the prior art with the result of the intermediate as
prepared by the present invention.
Table: 01
I I amino thiazole derivative by I I I
1 1 the process disclosed in the
-
S. No.
1
- - - -
Yield (%)
76.83
- -- - -
Process
Preparation of anhydrous
i
I amino thiazole derivative by 1 1 ~
-- - --
HPLC Purity (%)
97
1 2
present process
prior art
Preparation of anhydrous
Following is the comparison chart of the result of Cefdinir as prepared by
the process disclosed in the prior art with the result of Cefdinir as prepared by the
present inventive process.
Table: 02
- -- - - - - - - 1 S. NO. I Process 1 Y i e l d ( % j - ~ p l ~ P u r i t y ~ T a r k s ]
/ 1 / Preparation of Cefdinir as per 1 26.9 1 98 1 USP RS I
1 1 the prior art (using anhydrous 1 I 1 failed 1
I
1 2
1 anhydrous intermediate) 1 1 the present invention (using
All aspects of the present invention such as, temperature, reaction
conditions should be strictly followed to avoid the formation of impurities.
intermediate)
Preparation of Cefdinir as per 1 Passed 1
Certain aspects and embodiments of the present application are described
in further details by the examples below, which are provided only for the purpose
of illustration and are not intended to limit the scope of the application in any
manner.
The following abbreviations are used:
EHATA: Ethyl-2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate
HMDS: Hexamethyl disilazane
TMCS: Trimethylchlorosilane
7-AVCA: 7-amino-3-vinyl-3-cephem-4-carboxylic acid
USP: United States Pharmacopeia
RS: Reference Standard
38
EXAMPLE 1 : Preparation of sodium 2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate
dihydrate (syn-isomer)
I I
99 I USP RS
To a suspension of 20.0 Kg of ethyl-2-(2-aminothiazole-4-yl)-2-
hydroxyiminoacetate (EHATA) (syn-isomer) in 200.0 L of isopropanol is added
dropwise 4% aqueous sodium hydroxide (4.0 Kg sodium hydroxide in 100.0 L of
water) at a temperature of 35°C. to 40°C. under stirring over a period of one hour.
After addition, the stirring is continued for two hours at the same temperature till
completion of the reaction. The reaction mixture is cooled to a temperature of 0°C.
to 5°C. and after being stirred for one hour, the precipitate is collected by filtration,
washed with isopropanol, and dried under vacuum to obtain 18.8 Kg of sodium 2-
(2-aminothiazole-4-yI)-2-hydroxyiminoacetate dihydrate (syn-isomer) (HPLC
purity: 99.50%).
Example 2: Preparation 2-(2-aminothiazole-4-yl)-2-acetoxyiminoacetic acid (synisomer)
To a solution of 10.0 Kg of sodium 2-(2-aminothiazole-4-yl)-2-
hydroxyiminoacetate dihydrate (syn-isomer) in 70.0 L of water is added dropwise
acetic anhydride (6.85 Kg) at a temperature of 15°C. to 20 "C. under stirring over
a period of 60 minutes to 90 minutes . During the addition, the pH of the reaction
mixture is maintained in the range of pH 6.7 to pH 7.0 with 5% aqueous sodium
hydroxide solution. After 30 minutes stirring, the reaction mixture is acidified to pH
2.5 with 6N hydrochloric acid .The resulting precipitate is collected by filtration,
and washed with a mixture of water (10.0 L) and methanol (5.0 L) and then dried
under reduced pressure at 35°C. to 40 "C. to obtain hydrated 2-(2-aminothiazole-
4-yl)-2-acetoxyiminoacetic acid (syn- isomer) (1 0.0 Kg). (HPLC purity: 99.2 %;
moisture content: 13.5%).
Example 3: Preparation of (2Z)-[(acetyloxy)imino](2-amino-1,3-thiazol-4-yl)ethanoic
acid (monohydrate)
50.0 g of hydrated (2Z)-[(acetyloxy)imino](2-amino-I ,3-thiazol-4-yl)ethanoic
acid with a moisture content of 15.77% is suspended in methanol (500.0 mL) and
stirred for 15 hours at room temperature. The suspended solid is filtered, washed
with methanol (50.0 mL) and dried under reduced pressure to obtain (22)-
[(acetyloxy)imino](2-amino-1,3-thiazol-4-yl)ethanoic acid (monohydrate) (35.0 g).
(HPLC purity: 97.97; Moisture content: 7.78%).
Example 4: Preparation of anhydrous (22)-[(acetyloxy)imino](2-amino-I ,3-thiazol-
4-yl)ethanoic acid
50.0 g of hydrated (2Z)-[(acetyloxy)imino](2-amino-l,3-thiazol-4-yl)ethanoic
acid with a moisture content of 10.28% is suspended in methanol (500.0 mL) and
stirred for 10 minutes at room temperature. The suspension is heated to reflux at
65°C. to 66°C. for 5 hours. The reaction mixture is cooled to a temperature of 0°C.
to 5°C. The precipitated solid is filtered, washed with chilled methanol (50.0 mL)
and dried under reduced pressure to obtain anhydrous (22)-[(acetyloxy)imino](2-
amino-l,3-thiazol-4-yl)ethanoic acid (1 5.0 g). (HPLC purity: 99.37 ; Moisture
content: 0.4%).
Example 5: Preparation of anhydrous (22)-[(acetyloxy)imino](2-amino-1,3-thiazol-
4-yl)ethanoic acid
50.0 g of hydrated (2Z)-[(acetyloxy)imino](2-amino-1,3-thiazol-4-yl)ethanoic
acid with a moisture content of 10.28% is suspended in isopropyl alcohol (500.0
mL) and stirred for 10 minutes at room temperature. The suspension is heated to
reflux at 82°C. to 83°C. for 5 hours. The reaction mixture is cooled to a
temperature of 0°C. to 5°C. The precipitated solid is filtered, washed with chilled
isopropyl alcohol (50.0 mL) and dried under reduced pressure to obtain anhydrous
(2Z)-[(acetyloxy)imino](2-amino-ll3-thiazol-4-yl)ethanoic acid (1 0.0 g). (HPLC
purity: 95.40% ; Moisture content: 0.27%).
Example 6: Preparation of anhydrous (22)-[(acetyloxy)imino](2-amino-I ,3-thiazol-
4-yl)ethanoic acid
50.0 g of hydrated (2Z)-[(acetyloxy)imino](2-amino-I ,3-thiazol-4-yl)ethanoic acid
with a moisture content of 10.28% is suspended in a mixture of solvents methanol
(750.0 mL) and dichloromethane (1250.0 mL) and stirred for 10 minutes at room
temperature. The suspension is heated to a temperature of 40°C. to 45°C. to distill
out dichloromethane (1000.0 mL). The suspension is cooled to a temperature of
0°C. to 5°C. The solid is filtered, washed with chilled methanol (50.0 mL) and dried
under reduced pressure to obtain an anhydrous (2Z)-[(acetyloxy)imino](2-amino-
1,3-thiazol-4-yl)ethanoic acid (37.5 g). (HPLC purity: 97.75 %; Moisture content:
4.12%).
Example7: Preparation of anhydrous (2Z)-[(acetyloxy)imino](2-amino-I ,3-thiazol-
4-yl)ethanoic acid
50.0 g of hydrated (2Z)-[(acetyloxy)imino](2-amino-I ,3-thiazol-4-
yl)ethanoic acid with a moisture content of 10.28% is suspended in a mixture of
solvents isopropyl alcohol (750.0 mL) and dichloromethane (1250.0 mL) and
stirred for 10 minutes at room temperature. The suspension is heated to a
temperature of 55°C. to 60°C. to distill out dichloromethane (1000.0 mL). The
suspension is cooled to a temperature of 0°C. to 5°C. The solid is filtered, washed
with chilled isopropyl alcohol (50.0 mL) and dried under reduced pressure to
obtain anhydrous (22)-[(acetyloxy)imino](2-amino-I ,3-thiazol-4-yl)ethanoic acid
(42.5 g). (HPLC purity: 95.87%; Moisture content: 0.45%).
Example 8: Preparation of anhydrous (2Z)-[(acetyloxy)imino](2-amino-I ,3-thiazol-
4-yl)ethanoic acid
50.0 g of hydrated (2Z)-[(acetyloxy)imino](2-amino-1,3-thiazol-4-yl)ethanoic
acid with a moisture content of 15.77% is suspended in methanol (250.0 mL) and
stirred for 30 minutes at room temperature. The suspension is filtered and washed
with methanol (50.0 mL). The washed solid is suspended in tetrahydrofuran (500.0
mL), stirred for 10 minutes at room temperature and heated to reflux for 5 hours.
The suspension is cooled to a temperature of 0°C. to 5"C., and filtered. The
filtered solid is washed with chilled tetrahydrofuran (50.0 mL) and dried under
reduced pressure to obtain anhydrous (24-[(acetyloxy)imino](2-amino-1,3-thiazol-
4-yl)ethanoic acid (36.0 g). (HPLC purity: 99.36%; Moisture content: 0.34%).
Example 9: Preparation of anhydrous (2Z)-[(acetyloxy)imino](2-amino-I ,3-thiazol-
4-yl)ethanoic acid
50.0 g of hydrated (2Z)-[(acetyloxy)imino](2-amino-1,3-thiazol-4-yl)ethanoic
acid with a moisture content of 15.77% is suspended in tetrahydrofuran (500.0
mL) and stirred for 30 minutes at room temperature, and heated to reflux for 5
hours. The suspension is cooled to a temperature of 0°C. to 5"C., and filtered. The
filtered solid is washed with chilled tetrahydrofuran (50.0 mL) and dried under
reduced pressure to obtain anhydrous (2Z)-[(acetyloxy)imino](2-amino-I ,3-thiazol-
4-yl)ethanoic acid (3.5 Kg). (HPLC purity: 94.48%; Moisture content: 0.38%).
Example 10: Preparation of 2-(2-aminothiazol-4-yl)-2-acetoxyiminoacetyl chloride
hydrochloride (syn-isomer)
3.5 Kg of (2Z)-[(acetyloxy)imino](2-amino-I ,3-thiazol-4-yl)ethanoic acid is
suspended and stirred in methylene chloride (35.0 L), and cooled to a temperature
of -20°C. to -25°C. Phosphorous pentachloride (4.0 Kg) is added, and reaction is
maintained for 15 hours at -20°C. to -25°C. under nitrogen atmosphere. The
precipitated solid is filtered, washed with methylene chloride (14.0 L) to obtain 2-
(2-aminothiazol-4-yl)-2-acetoxyiminoacetyl chloride hydrochloride (syn-isomer)
(4.3 Kg (wet)).
Example 11 : Preparation of 7-[2-(2-aminothiazol-4-yl)-2-acetoxyiminoacetamido]-
3-vinyl-3-cephem-4-carboxylic acid (syn-isomer)
To a suspension of 2.85 Kg of acetamide and 3.30 Kg of hexamethyl
disilazane (HMDS) in 20.0 L of dichloromethane is added 0.0168 Kg of
trimethylchlorosilane (TMCS). The suspension is maintained to reflux at 55°C. to
58°C for 15-20 hours. After completion of the reaction, 2.331 Kg of 7-amino-3-
vinyl-3-cephem-4-carboxylic acid (7-AVCA) and 14.04 L of dichloromethane are
charged under nitrogen blanketing, refluxed for 60 minutes. To the reaction mass,
cooled to a temperature of -20°C. to -25"C., added 4.30 Kg (wet material) of 2-
(2-aminothiazol-4-yl)-2-acetoxyiminoacetyl chloride hydrochloride (syn-isomer),
and stirred for 120 minutes at -20°C. to -25°C.. After completion of the reaction,
water (46.6 L) is added to the reaction mass, the resulting solid is filtered, washed
with cold water (20.0 L), and dried under reduced pressure to obtain 8.8 Kg of 7-
[2-(2-aminothiazol-4-yl)-2-acetoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic
acid (syn-isomer).
Examplel2: Preparation of Cefdinir
7.0 Kg of 7-[2-(2-aminothiazol-4-yl)-2-acetoxyiminoacetamido]-3-vinyl-3-
cephem-4-carboxylic acid (syn-isomer) is suspended in 50.0 L of water, and
cooled to 15°C. to 20°C. The solid is dissolved by drop wise addition of 20%
aqueous potassium carbonate (5.55 Kg of potassium carbonate in 28.0 L of
water). 2.3 Kg of ammonium chloride is added to the reaction mass. The pH of
reaction mass is adjusted to 8.0 to 8.2 with 20 % aqueous potassium carbonate at
15°C. to 20°C. till the completion of the reaction. After completion of the reaction,
potassium acetate (7.0 Kg) is added, the reaction mass is cooled to a 0°C. to
5"C., and stirred for 120 minutes to isolate wet cefdinir potassium salt (3.4 Kg).
The above wet cefdinir potassium salt is dissolved in 130.0 L of water at a
temperature of 25°C to 30°C. The solution is treated with 0.25 Kg of activated
carbon and stirred for 30 minutes. The solution is filtered through celite bed,
washed with 10.0 L of water. The pH of the filtrate is adjusted to 2.2 to 2.3 with
dilute sulfuric acid (10%w/v). The resulting solid is filtered, and dried to obtain
crystalline cefdinir form A. (2.95 Kg) (HPLC purity: 99.1 6%; Moisture content:
1.322%, Yield: 34%).
Example1 3: Preparation of Cefdinir
5.0 Kg of 7-[2-(2-aminothiazol-4-yl)-2-acetoxyiminoacetamido]-3-vinyl-3-
cephem-4-carboxylic acid (syn-isomer) is suspended in 30.0 L of water, and
cooled to 15°C. to 20°C. The solid is dissolved by drop wise addition of 20%
aqueous potassium carbonate (3.96 Kg of potassium carbonate in 20.0 L of
water). 1.65 Kg of ammonium chloride is added to the reaction mass. The pH of
reaction mass is adjusted to 8.0 to 8.2 with 20 % aqueous potassium carbonate at
15°C. to 20°C. till the completion of the reaction. After completion of the reaction,
potassium acetate (5.0 Kg) is added, the reaction mass is cooled to a -5°C. to
O°C., and stirred for 120 minutes to isolate wet cefdinir potassium salt (2.5 Kg).
The above wet cefdinir potassium salt is dissolved in 93.0 L of water at a
temperature of 25°C to 30°C. The solution is treated with 0.20 Kg of activated
carbon and stirred for 30 minutes. The solution is filtered through celite bed,
washed with 10.0 L of water. The pH of the filtrate is adjusted to 2.2 to 2.3 with
dilute sulfuric acid (10%w/v). The resulting solid is filtered, and dried to obtain
crystalline cefdinir form A. (2.46 Kg) (HPLC purity: 99.16%; Moisture content:
1.322%, Yield: 38%).

We claim:
1. A process for the preparation of anhydrous thiazole derivative of Formula I,
FORMULA l
H2N N-0
comprising one or more of the following steps, individually or in the
sequence recited:
i. suspending hydrated thiazole derivative of Formula IV,
H2N . 2 ~ * 0 FORMULA IV
N-0
in a suitable solvent;
ii. optionally, refluxing suspension of step i);
iii. optionally, cooling suspension of step ii);
iv. filtering suspension of step iii);
v. washing solid, as obtained from step iv), with suitable solvent;
vi.drying solid, as obtained from step v), to obtain anhydrous thiazole
derivative of Formula I; and
vii.optionally, using anhydrous thiazole derivative of Formula I in the
preparation of cefdinir of Formula II.
FORMULA ll
2. The process according to claim 1, wherein suitable solvents of step i) and
step v) are selected from an alcohol such as methanol, ethanol,
isopropanol, n-propanol, n-butanol, and 2-butanol; a halogenated
hydrocarbon such as dichloromethane, ethylene dichloride, and chloroform;
an ether such as diethyl ether, diisopropyl ether, methyl t-butyl ether,
tetrahydrofuran, and dioxane; or mixtures thereof.
3. The process according to claim 1, wherein suitable time for refluxing the
suspension in the step i) is less than 10 hours, preferably less than 5 hours,
and more preferably less than 1 hour.
4. The process according to claim 1, wherein washing of solid in step v) is
carried out with chilled solvent.
5. The process according to claim I , wherein drying in step vi) is carried out at
temperature less than 100°C., more preferably less than 60°C, and most
preferably less than 40°C.
6. The process according to claim 1, wherein drying period in step vi) is
preferably 01 to 15 hours, or more preferably longer than 15 hours.
7. The process according to claim 1, wherein drying in step vi) is carried out
by using techniques such as tray drying, vacuum drying, air drying,
fluidized bed drying, spin flash drying, flash drying, spray drying, thin film
drying, and freeze drying, or combination thereof.
8. The process according to claim 1, wherein drying in step vi) is carried out at
atmospheric pressure or under reduced pressure.
9. The process according to claim 1, wherein drying in step vi) is carried out in
the presence or absence of an inert atmosphere which can be of nitrogen,
argon, neon, or helium.
10. A process for the preparation of anhydrous thiazole derivative of Formula I,
FORMULA I
H2N N-0
comprising following steps, in the sequence recited:
i. suspending hydrated thiazole derivative of Formula IV,
H2N . 2 ~ ~ 0FO RMULA IV
N-q
in suitable solvent;
ii. refluxing suspension of step i);
iii. cooling suspension of step ii);
iv. filtering suspension of step iii);
v. washing solid, as obtained from step iv), with suitable solvent;
vi. drying solid, as obtained from step v), to obtain anhydrous thiazole
derivative of Formula I; and
vii. using anhydrous thiazole derivative of Formula I in the preparation of
cefdinir of Formula II.