The present invention provides a process for the preparation of Faropenem.
(5R,6S)-6-[(1 R)-1-hydroxyethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, commonly known as faropenem of Formula I is a synthetic, broad-spectrum, carbapenem antibiotic.
(Formula Removed)
Sodium salt of faropenem shows potent antibacterial activity against methicillin-sensitive Staphylococcus aureus (MSSA), Streptococcus pyrogenes and Streptococcus pneumoniae 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 influenzas and anaerobic bacteria such as the genus Bacteroides.
US Patent No 4,997,829 provides processes for the preparation of sodium and potassium salts of faropenem, wherein the process involves deprotection of allyl faropenem in the presence of triphenylphosphine, palladium tetrakis-triphenylphosphine and sodium or potassium 2-ethylhexanoate. However, the process disclosed in '829 patent does not involve the use of water and therefore, it does not result in stable and commercially useful hydrates of faropenem salts.
EP Patent No 0,410,727 provides various processes for preparing hemipentahydrate of faropenem salts, wherein the processes involve deprotection of allyl faropenem in the presence of an alkali metal enolate of 1,3-diketone. The faropenem formed in situ is converted into hemipentahydrate by the addition water. JP Patent No 2,949,363 B2 also provides a process for preparing hydrates- of faropenem salts by treating deprotected faropenem with alkali metal salt of a C1-4 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.
While working on this problem, the present inventors have developed an advantageous process for the preparation of hydrates of alkali metal salts of faropenem. The present process does not involve the removal of water and it provides the hydrates of faropenem with higher yield, reduced time cycle and greater purity rendering the process economical and industrially viable.
A first aspect of the present invention provides a process for preparation of a hydrate of an alkali metal salt of faropenem, wherein the said process comprises,
a) treating the compound of Formula II,
(Formula Removed)
wherein Ri is selected from a group comprising of optionally substituted C1-C8 alkyl, optionally substituted C3-C8 alkenyl or optionally substituted C7-C19 aralkyl, optionally substituted C6-C12 aryl,
with an alkali metal salt of a substituted or unsubstituted C5-10 carboxylic acid and catalytic amount of a palladium complex in the presence of an organic solvent,
b) treating the reaction mixture of step a) with water and a water miscible solvent,
c) isolating a hydrate of an alkali metal salt of faropenem from the reaction mass thereof,
wherein the process is characterized by the fact that water is not removed from the
reaction mixture in step b) or c).
The compound of Formula II can be prepared according to the methods provided in the prior arts mentioned above. The compound of Formula II is dissolved in an organic solvent. The organic solvent is selected from a group comprising of dichloromethane, dichloro ethane, chloroform, methyl acetate, ethyl acetate, tetrahydrofuran, diethyl ether, methanol, ethanol, acetonitrile, propionitrile, acetone or methyl ethyl ketone. The solution so obtained is treated with an alkali metal salt of a substituted or unsubstituted C5-10 carboxylic acid and catalytic amount of a palladium complex. The C5-10 carboxylic acid can be 2-ethylhexanoic acid, pentanoic acid, hexanoic acid or heptanoic acid. The acid can be used in the form of an alkali metal salt or an alkali metal hydroxide together with C5-10 carboxylic acid can be used. The palladium complex can be selected from a group comprising of tetrakis(triphenylphosphine) palladium (O), bis(triphenylphosphine) palladium (II) dichloride, dichloro-di-(benzonitrile palladium (II), or palladium diacetate. The palladium complex is used together with a phosphine ligand such as triarylphosphine.
An addition of water to the reaction mixture helps in the formation of the hydrates of faropenem salt. An addition of a water miscible solvent to the reaction mixture facilitates the precipitation of the hydrate. The water miscible solvent can be selected from a group comprising of acetone, tetrahydrofuran, methanol, ethanol, isopropyl alcohol, dioxane or acetonitrile. The hydrate of alkali metal salt of faropenem can be isolated from the reaction mixture by filtration.
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.
EXAMPLE 1
PREPARATION OF FAROPENEM SODIUM HEMIPENTAHYDRATE:
Allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylate (72 g, 0.221 mol) was dissolved in methylene chloride (950 ml). The solution was cooled to 10°C and triphenyl phosphine (2.0 g, 0.0076 mol), sodium-2-ethylhexanoate (39.71 g, 0.239 mol) and tetrakis triphenylphosphine palladium (0) (2.0 g) were added together at 10°C. The reaction mixture was stirred for 1-2 hours at 10-15°C. After the completion of reaction, water (50 ml) was added to the
reaction mixture. The reaction mixture was stirred for 15 minutes, followed by the addition
of acetone (332.5ml) and the reaction mixture was cooled to 0°C. The solid so separated
from the reaction mixture was filtered, washed with acetone and dried under reduced
pressure to obtain the title compound.
Yield: 64 g
Purity by HPLC: 99.0%

WE CLAIM:
1. A process for preparation of a hydrate of an alkali metal salt of faropenem, wherein the
said process comprises,
a) treating the compound of Formula II,
(Formula Removed)
wherein R1 is selected from a group comprising of optionally substituted C1-C8 alkyl, optionally substituted C3-C8 alkenyl, optionally substituted C7-C19 aralkyl, optionally substituted C6-C12 aryl,
with an alkali metal salt of a substituted or unsubstituted C5-10 carboxylic acid and catalytic amount of a palladium complex in the presence of an organic solvent,
b) treating the reaction mixture of step a) with water and a water miscible solvent,
c) isolating a hydrate of an alkali metal salt of faropenem from the reaction mass
thereof,
wherein the process is characterized by the fact that water is not removed from the reaction mixture in step b) or c).
2. A process as claimed in claim 1, wherein the hydrate of an alkali metal salt of
. faropenem is faropenem sodium hemipentahydrate.
3. A process as claimed in claim 1, wherein the C5-10 carboxylic acid is 2-ethylhexanoic
acid.
4. A process as claimed in claim 1, wherein the palladium complex is selected from a
group comprising of tetrakis(triphenylphosphine) palladium (O),
bis(triphenylphosphine) palladium (II) dichloride, dichloro-di-(benzonitrile palladium (II),
or palladium diacetate.
5. A process as claimed in claim 4, wherein the palladium complex is
tetrakis(triphenylphosphine) palladium (O).
6. A process as claimed in claim 1, wherein the organic solvent is selected from a group
comprising of dichloromethane, dichloro ethane, chloroform, methyl acetate, ethyl
acetate, tetrahydrofuran, diethyl ether, methanol, ethanol, acetonitrile, propionitrile,
acetone or methyl ethyl ketone.
7. A process as claimed in claim 1, wherein the palladium complex is used along with a
phosphine ligand.
8. A process as claimed in claim 7, wherein the phosphine ligand is triaryl phosphine.
9. A process as claimed in claim 1, wherein the water miscible solvent is selected from a
group comprising of acetone, tetrahydrofuran, methanol, ethanol, isopropyl alcohol,
dioxane or acetonitrile.
10. A process as claimed in claim 9, wherein the water miscible solvent is acetone.