FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
AN IMPROVED PROCESS FOR PREPARATION OF FEROPENEM SODIUM AND HYDRATE THEREOF"
We, CADILA HEALTHCARE LIMITED, of Zydus Research Centre, "Zydus Tower", Satellite Cross Road, Ahmedabad - 380 015, Gujarat, INDIA.
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of faropenem sodium and hydrate thereof.
BACKGROUND OF THE INVENTION:
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
(5R,6S)-6-[(lR)-l-hydroxyethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-aza bicyclo [3.2.0]hept-2-ene-2-carboxylic acid, commonly known as faropenem of Formula I is a synthetic, broad-spectrum, Carbapenem antibiotic.

The sodium salt of faropenem shows potent antibacterial activity against me-thicillin-sensitive Staphylococcus aureus (MSSA), Streptococcus pyrogenes and Streptococcus pneumonia and gram-positive bacteria such as penicillin-resistant pneumococci (PRSP), oral staphylococci and enterococci. It also shows a wide antibacterial spectrum covering gram-negative bacteria such as Haemophilus influenza and anaerobic bacteria such as the genus Bacteroides.
U.S. Patent No 4,997,829 provides a process for the preparation of sodium and potassium salts of faropenem, involving the deprotection of allyl faropenem in the presence of triphenylphosphine, palladium tetrakis-triphenylphosphine and sodium or potassium 2-ethylhexanoate. However, the process disclosed in the '829 patent does not result in stable and commercially useful hydrates of faropenem salts.
EP Patent No. 410,727 provides various processes for preparing the hemipentahydrate of faropenem salts, involving the deprotection of allyl faropenem in the presence of an alkali metal enolate of 1,3-diketone. The hemipentahydrate salt of faropenem salt is characterized by Single Crystal X-ray analysis, 1H NMR, IR, specific optical rotation and elemental analysis. The faropenem formed in situ is converted into hemipentahydrate by the addition
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water. JP Patent No 2,949,363 B2 also provides a process for preparing hydrates of faropenem salts by treating deprotected faropenem with an alkali metal salt of aCw carboxylic acid in the presence of water.
The water added to the reaction mixture to effect the formation of hydrates in the prior art processes is removed by distillation. However, the removal of water from the reaction mixture under reduced pressure consumes both time and energy. Additionally the solution stability of faropenem sodium in water is very poor and prolonged storage or heating results in impurity formation.
CN 1733771 A discloses the process for the preparation of feropenem sodium from reaction by-products. Feropenem sodium prepared from 4-AA i.e. Acetic acid 3-[l-(tert-butyl)-dimethyl silanyloxy)-ethyl]-4-oxo-azetidinone-2-yl ester via allylation, intermolecular wittig reaction and deallylation results in Feropenem sodium also results in byproducts like below like syn and anti isomer. The reaction sequence is depicted in Scheme-1 as shown below.


TBSO
H,C

H3C
TBSO

SCHEME-1
The byproducts syn and anti isomers produced during the reaction are as shown below which are again used to prepare feropenem sodium

SYN

3
ANTI

CN 1884284 discloses the method for the preparation of feropenem sodium which comprises of: (1) performing reaction in the presence of the intermediate compound. I (R2 = H, halo, alkyl, or alkyoxy) with optical grade 2-(R)-tetrahydrofuran thiocarbonic acid in the presence of base to obtain compound II; (2) reacting with allyl glyoxylate by heating and refluxing to obtain compound III; (3) converting to chloride and performing intramolecular Wittig reaction, after removing protective group to obtain sodium feropenem. The invention also discloses the manufacture of the intermediate compound I.

CN 1733772 discloses one-pot synthesis of Feropenem sodium which involves (a) condensing (R)-tetrahydrofuran-2-thioformic acid and (3R,4R,l'R)-4-acetoxy-3-(l-tert-butyldimethylsilicoxy)ethyl)azetidinone-2-one (4AA) in a solvent at -20°C to 60°C for 0.5-24 h in the presence of base; (b) condensing product of (a) with allyl chlorooxoacetate in solvent at -20°C to 60°C for 1-24 h in the presence of organic base like triethylamine or pyridine; (c) carrying out intramolecular Wittig or Wittig-Horner reaction of product of (b) with triphenylphosphine or tri-ethyl phosphite; (d) deprotecting with dil. HC1 of HF, or tetrabutylammonium fluroide; (e) reacting with sodium 2-ethylcaproate in the presence of Pd(PPh3)4 in ethyl ether at 10°C to 80°C for 2-36 h, filtering to obtain crude product, and recrystallizing with water/acetone to obtain pure product; wherein the operation a and b or c and d can be exchanged.
The main disadvantage associated with the one-pot process disclosed herein is use of different solvent as different stages. Also, the use of ethyl ether during deallylation is not industrially viable process. The continuos process like the one provided above will always
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have impurities, unreacted starting materials etc. which is carry forwarded till the final step. Hence, the feropenem sodium pentahemihydrate resulted will not have every individual impurity less than 0.1 % as per ICH guidelines. Also, the yield factor will vary from step to step which will results in inconclusive yields. Thus, there is a need to isolate atleast one of the intermediate which will by having better yield and purity. Thus, it is the scope of the present invention to obtain Allyl (5R,6S)-6-[(lR)-l-(t-butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in better purity and yield. The present invention also provides a process for preparation of pentahemihydrate salt of feropenem sodium from Allyl (5R,6S)-6-L(lR)-l-(t-butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-azabicyclo[3.2.0] hept-2-ene-2-carboxylate in one pot synthesis.
WO 2007/039885 Al discloses the process for the preparation of hydrate of an alkali metal salt of feropenem wherein the process comprises reacting protected feropenem with an alkali metal salt of a substituted or unsubstituted C5.10 carboxylic acid an a catalytic amount of a palladium in the presence of an organic solvent followed by treatment with water and a water miscible organic solvent and isolating a hydrate of an alkali metal salt of feropenem from the reaction mixture wherein water is not removed from the reaction mixture.
A hydrate of the sodium salt of a penem carboxylic acid like feropenem sodium is disclosed in Acta Crystallographica, Section C; crystal Structure communications (1994), C50(8), 1254-6. The crystalline nature of the compound is confirmed by single crystal analysis disclosing the hemipentahydrate of feropenem sodium, a member of a new class of p-lactam antibiotics, is orthorhombic, space group P2,2,2, with a 9.208 (1), b 32.454(2), c 5.495(3) A; Z = 4, dc = 1.43, R = 0.059, Rw = 0.110 for 1592 reflections.
To overcome the drawbacks of the prior art process the present invention relates to provide a simple, cost effective, non-hazardous and easily scaleable at large commercial production process for preparation of crystalline ammonium salt of (E)-7-[4-(4-flourophenyl) isopropyl-2-[methyl(methysulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid.
OBJECT OF THE INVENTION:
It is an object of the present invention in its preferred form to provide an improved process for preparation of feropenem sodium and hydrate thereof.
Another object of the present invention is to provide a one-pot process for the preparation of feropenem sodium and hydrate thereof.
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Further object of the present invention is to overcome the problems associated with the prior art process and to prepare pure feropenem sodium alkali metal salt and hydrate thereof by simple, cost effective, non-hazardous, easily scaleable and industrially viable process.
SUMMARY OF THE INVENTION:
There is provided a one-pot process for the preparation of alkali metal salts of Feropenem. The present inventors has developed advantageous processes for preparation of alkali metal salts of feropenem and hydrates thereof in a one pot process avoiding the tedious work-up procedure and isolation of the intermediates at each stage.
According to one embodiment, the present process provides a common medium to obtain intermediate compounds finally to give alkali metal salt of feropenem and hydrate thereof avoiding the use of different organic solvents at different stages and performing tedious work-up procedures, to obtain higher yield by checking the conversion of key intermediates by TLC. The total yield is approximately greater than 99% on TLC.
According to one another embodiment, the present invention provides directly insitu hydrate of alkali metal salt of feropenem i.e. 2.5 hydrate whereby process doesn't involve the removal of water and it provides the hydrate of feropenem with higher yield, reduced time cycle and greater purity.
The process of the invention avoids critical steps such as distillation, change of solvent systems etc. and is therefore economically and industrially viable.
DESCRIPTION OF THE INVENTION:
In one aspect, a one pot process for preparation allyl (5R,6S)-6-[(lR)-l(t-butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-azabicyclo[3.2.0] hept-2-ene-2-carboxylate of formula II

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wherein the process comprises:
a) condensing (3R,4R,l'R)-4-acetoxy-3-(l-(t-butyldimethylsilicoxy)ethyl)azetidin-2-one (4-

AA) of formula III
Formula III
and (2R)-tetrahydro-2-furancarbothioic S-acid; sodium salt of formula IV

in a solvent at -10°C to 20°C for 0.5 to 2.0 hrs in a molar ratio of 1:1.1 to 1:1.5 in presence of base;
b) condensing product of (a) with allyl chlorooxoacetate in a solvent at -25°C to 25°C for 1-10 hrs in a molar ratio of 1:1.2 to 1:1.8 with respect 4-AA of formula III in presence of organic base;
c) carrying out intramolecular Wittig of Wittig-Horner reaction of product (b) with triphenyl phosphine or tri-ethylphosphite in a solvent at reflux temperature for 0.5-10 hrs;
d) removing the solvent to obtain the residue;
e) treating the residue with suitable organic solvent and heated at 40°C to 80°C for 0.5-2 hrs;
f) gradually cooling to 0°C to 5°C to precipitate the product; and
g) isolating the product.
The condensation of compound azetidinone 4-AA of formula III and (2R)-tetrahydro-2-furancarbothioic S-acid; sodium salt of formula IV as in step (a) can be done in organic solvent selected from THF, Xylene, Toluene or mixture thereof with water, preferably in a mixture of toluene and water at -10°C to 20°C, preferably at 0°C to 10°C for 0.5-2.0 hrs, preferably for 0.5 hrs till the pH of the reaction mixture is 10.5 to 11.5.
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The compounds azetidinone 4-AA of formula III and (2R)-tetrahydro-2-furancarbothioic S-acid, sodium salt of formula IV were taken in the molar ratio of 1:1.2 to 1:1.8 with respect 4-AA of formula III, preferably 1:1.2 to 1:1.5, more preferably 1:1.25 in presence of base like inorganic base like carbonate, bicarbonate, hydroxides etc. carbonate like alkali metal carbonates, bicarbonates like alkali metal or alkaline earth metal bicarbonates etc. hydroxides like alkali metal hydroxides, preferably sodium or potassium hydroxide, more preferably sodium hydroxide.
The base used during the condensation reaction is 10% solution of sodium hydroxide to adjust the alkaline pH from about 10.5 to about 11.5.
The condensation of intermediate product of step (a) with allyl chlorooxoacetate as in step (b) can be done in can be done in organic solvent selected from THF, Xylene, Toluene or mixture thereof with water, preferably in a mixture of toluene and water at -25°C to 25°C, preferably at -25°C to -5°C, more preferably from -18°C to -22°C for 1-10 hrs preferably 1-5 hrs or till the completion of the reaction as checked by TLC.
Allyl chlorooxoacetate is used in the molar ratio of 1:1.2 to 1:1.8, preferably 1:1.25 to 1:1.6, more preferably 1:1.5 with respect 4-AA of formula III in presence of organic base selected from the group of alkyl amines or pyridine, more preferably alkyl amine like triethyl amine.
The intramolecular Wittig or Horner-Wittig reaction for the preparation of allyl (5R,6S)-6-[(lR)-l(t-butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylate of formula II is done by using triphenyl phosphite or triphenyl phosphine, preferably triphenyl phosphite in a solvent done in organic solvent selected from THF, Xylene, Toluene or mixture thereof with water, preferably in toluene at reflux temperature for 0.5-10 hrs.
The in situ product residue obtained after the removal of toluene i.e. allyl (5R,6S)-6-[(lR)-l(t-butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-aza-bicyclo[3.2.0] hept-2-ene-2-carboxylate of formula II is treated with suitable organic solvent selected from the group of C1-C4 alcohols like methanol, ethanol, propanol, isopropanol and butanol, ethers like dioxane, THF etc. esters like methyl acetate, ethyl acetate etc. ketones like methyl isobutyl ketone, methyl ethyl ketone, acetone etc. preferably with alcoholic solvent like isopropanol at heated at 40°C to 80°C, preferably at 50°C to 55°C for 0.5-2 hrs and is gradually cooled to 0°C to 5°C to obtain pure allyl (5R,6S)-6-[(lR)-l(t-
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butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-aza-bicyclo[3.2.0] hept-2-ene-2-carboxylate having purity greater than or equal to 99% by HPLC.
The product allyl (5R,6S)-6-[(lR)-l(t-butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-aza-bicyclo[3.2.0] hept-2-ene-2-carboxylate of formula II is an important precursor for the preparation of antibiotics like feropenem. Hence, it is further aspect of the present invention to provide hydrate of alkali metal salt of feropenem in high yield and purity by using the pure intermediate of formula II.
In another aspect, there is provided one-pot process for the preparation of hydrate of alkali metal salt of feropenem of formula I

COOR nH20
wherein R is alkali metal or alkaline earth metal salt and n is 2.5 comprises:
a) reacting allyl (5R,6S)-6-[(lR)-l(t-butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydro-furan-2-yl]-4-thia-l-azabicyclo[3.2.0] hept-2-ene-2-carboxylate of formula II

Formula II
with deprotecting reagent in a molar ratio of 1:1.2 to 1:1.8 with respect to compound of formula II in presence of an acid in a suitable organic solvent at 20°C to 80°C for 1-20 hrs;
b) cooling the reaction mixture;
c) treating with a mixture of water and water immiscible organic solvent;
d) removal of organic solvent to obtain the residue;
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e) reacting the residue with sodium 2-ethylcaproate in the presence of Pd(PPh3)4 and
triphenyl phosphine in suitable organic solvent at an ambient temperature;
f) isolating the technical feropenem sodium;
h) optionally purifying technical feropenem sodium in alcoholic solvent;
i) removal of alcoholic solvent to obtain the residue; and
j) treatment of residue with mixture of water and acetone and isolating pentahemihydrate of feropenem sodium.
The compound allyl (5R,6S)-6-[(lR)-l(t-butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydroturan-2-yl]-4-thia-l-aza-bicyclo[3.2.0] hept-2-ene-2-carboxylate of formula 11 is treated with a deprotecting agent to remove the hydroxy protecting group like t-butyldimethylsilicoxy, where the suitable deprotecting agents can be selected from dil HC1, HF or tetrabutyl ammonium fluoride (TBAF), more preferably tetrabutyl ammonium fluoride in a molar ratio of 1:1.2 to 1:1.8, preferably 1:1.4 to 1:1.6, more preferably 1:1.47 with respect to compound of formula II.
The deprotection of silylprotected hydroxy group is done in presence of acid like acetic acid in a suitable organic solvent selected from the group of C1-C4 alcohols like methanol, ethanol, propanol, isopropanol and butanol, ethers like dioxane, THF etc. esters like methyl acetate, ethyl acetate etc. ketones like methyl isobutyl ketone, methyl ethyl ketone, acetone etc. preferably in acetone at 20°C to 80°C, preferably at 45°C to 50°C for 1-20 hrs, more preferably for 16-18 hrs. The reaction mixture was cooled and treated with mixture of water and water immiscible organic solvent like toluene, methylene dichloride, ethyl acetate etc. more preferably mixture of water and methylene dichloride.
The unisolated desilylated derivative of compound of formula II is treated with sodium 2-ethylcaproate in the presence of Pd(PPh3)4 and triphenyl phosphine in suitable organic solvent like THF at an ambient temperature to obtain the technical feropenem sodium which can be optionally purified by alcoholic solvents like C1-C4 alcohols like methanol, ethanol, propanol, isopropanol and butanol, preferably methanol.
The hydrate s of alkali metal salt of feropenem i.e. feropenem sodium is prepared by treating the technical feropenem sodium with mixture of water and acetone. The hydrate thus obtain is pentahemihydrate of feropenem sodium. The pentahemihydrate of feropenem sodium thus obtained is having purity greater than 99.0% and all individual impurities less than 0.1%. The total impurities is less than 0.5%.
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It is preferred that the feropenem sodium particles D50 not exceeding 100 /mi. It is noted the notation Dx means that X% of the particles have a diameter less than a specified diameter D. Thus a D50 of 100 mm means that 50% of the particles in feropenem sodium preferably have a diameter less than 100 mm, preferably D50 is less than 75 mm.
A preferred mean particle size of feropenem sodium particles is equal to or less than 75 //m. The range of mean particle sizes preferred for use in the invention is 30 to 75 /mi, more preferably 35 to 70 mm, and most preferably 45 to 65 //m, The particle sizes stipulated herein and refer to particle sizes determined with Malvern light scattering.
The term "particles" refers to individual particles whether the particles exist singly or are agglomerated. Thus, feropenem sodium comprising particulate feropenem sodium pentahemihydrate may contain agglomerates that are well beyond the size limit of about 75 mm specified herein. However, if the mean size of the primary drug substance particles (i.e., feropenen sodium or feropenem sodium pentahemihydrate) comprising the agglomerate are less than about 75 mm individually, then the agglomerate itself is considered to satisfy the particle size constraints defined herein and the composition is within the scope of the invention.
Reference to feropenem sodium or to feropenem sodium pentahemihydrate particles having "a mean particle size" (herein also used interchangeably with "VMD" for "volume mean diameter") equal to or less than a given diameter or being within a given particle size range means that the average of all feropenem sodium particles in the sample have an estimated volume, based on an assumption of spherical shape, less than or equal to the volume calculated for a spherical particle with a diameter equal to the given diameter i.e. VMD D[4,3] < 175 /mi, preferably < 150 /mi. Particle size distribution can be measured by Malvern light scattering as known to those skilled in the art and as further disclosed and discussed below.
Although the invention has been described with reference to a specific example, it will be appreciated by those skilled in the art that the invention may be embodied in many other forms.
The process of the present invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be constructed as limit to the scope of the claims in any manner.
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Examples:
Example-1: One-pot preparation of Allyl (5R,6S)-6-[(lR)-l(t-butyldimethylsilicoxy)
ethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-
carboxylate

1.0 Kg of (3R,4R,l'R)-4-acetoxy-3-(l-t-butyldimethylsilicoxy)ethyl)azetidin-2-one (4-AA) was taken in mixture of 15.0 L toluene and 5.0 L water at 25°C to 35°C. The reaction mixture was cool down up to 0°C to 10°C and 0.67 Kg of (2R)-tetrahydro-2-furancarbothioic S-acid; sodium salt was added. The reaction was proceeded in basic pH of 10.5 to 11.5 by adding 10% sodium hydroxide solution. The extracted organic layer of toluene was washed with water and filtered. The toluene layer was distilled and cooled after distillation. 0.524 Kg of triethylamine was added at 25°C to 35°C and cooled down below -20°C. 0.770 Kg of allyl chlorooxoacetate in 2.48 L of toluene was added within 3 hrs and stirred. The reaction mixture was treated with 9.5 L of water at -18°C to 22°C. The organic layer was washed with water and filtered through hyflow bed. The toluene layer was distilled and the reaction mass was cooled. 1.60 L of triethyl phosphite was added and heated to reflux for 6-8 hrs. The toluene was distilled to obtain the residue which was treated with 3.20 L of isopropanol and heated and gradually cooled to 0°C to 5°C. The product was filtered and washed with chilled isopropanol to obtain Allyl (5R,6S)-6-[(lR)-l(t-butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
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ExampIe-2: Preparation of Feropenem Sodium

100 gm Allyl (5R,6S)-6-[(lR)-l(t-butyldimethylsilicoxy)ethyl]-7-oxo-3-[(2R)-tetrahydro furan-2-yl]-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate, 820 mL acetone, 57.6 gm of acetic acid were taken 1L of round bottom flask. 87.4 gm of tetrabutyl ammonium fluoride solution in 340 mL acetone was added dropwise within 30 min. The reaction mixture was heated upto 45°C-50°C for 16-18 hrs. The cooled reaction mixture was treated with mixture of 1L of water and 1L of methylene dichloride and stirred for 30 min. The separated organic layer was washed with water. Methylene dichloride was completely distilled to obtain 80.90 gm of Allyl (5R,6S)-6-[(lR)-l-hydroxyethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-azabicyclo [3.2.0]hept-2-ene-2-carboxylate as wet residue.
500 mL THF was added to above residue and stirred. 16.0 gm triphenyl phosphine, 4.2 gm of tetra kis(triphenylphosphine)Palladium, 34.0 gm sodium 2-ethylhexanoate within 15-20 min and 20.4 gm of water were added and stirred. Solid thus obtained was filtered and washed with THF. The product was dried under vacuum at 45°C to 50°C to obtain 64.0 gm technical Feropenem Sodium.
62.0 gm of technical feropenem sodium was taken in 200 mL of methanol to obtain clear solution. The reaction mixture was charcoalized, filtered and washed with methanol. Methanol was distilled. The residue 69.64 gm was treated with mixture of 30.0 mL of water and 90.0 mL of acetone at 25°C to 30°C. The reaction mixture was stirred for 2 hrs and cooled to 0°C to 5°C. The product was filtered and washed with chilled acetone. The product was dried at 45°C to 50°C under vacuum to obtain 53.0 gm of Feropenem Sodium Pentahemihydrate.
Dated this the 16th day of June 2007.

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