FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
COMPLETE SPECIFICATION
A Process for Preparation of Ertapenem SeQuent Scientific Limited
A Company Incorporated Under The Companies Act, 1956
Having Registered Office at 301, 'Dosti Pinnacle', 3rd Floor,
Plot No.E7, Road No.22, Wagle Industrial Area,
Thane (W)-400 604
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION
The present invention relates to a novel process for the preparation of 1β-methylcarbapenem antibiotic, Ertapenem of formula I.

BACKGROUND OF THE INVENTION
Ertapenem is a sterile, synthetic, parenteral, 1-β methyl-carbapenem that is structurally related to beta-lactam antibiotics. It is marketed by Merck as Invanz®. It is structurally very similar to Meropenem in that it possesses a 1-β methyl group. Ertapenem is used as antibiotic agent in the treatment of moderate to severe complicated foot infection due to indicated pathogens in diabetic patients without osteomyelitis, and also useful in the treatment of pneumonia, urinary tract infections, intra-abdominal, gynaecological, skin, and soft tissue infections, meningitis, septicaemia and febrile Neutrogena.
A number of synthetic processes are reported for the preparation of ertapenem. US
patent 5,478,820 describes a process for preparation of ertapenem by condensing 1-
Azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, 3-[(diphenoxyphosphinyl)oxy]-6-(l-
hydroxyethyl)-4-methyl-7-oxo-,(4-nitrophenyl)methyl ester, [4R-[4a,5b,6b(R*)]] (MAP) (25 g) and ertapenem side chain -[(2S,4S)-4-Mercaptopyrrohdine-2-carboxamido]benzoic acid hydrochloride to obtain a diprotected ertapenem. The diprotected ertapenem is deprotected using palladium on carbon and the obtained ertapenem is isolated by using column purification as well as freeze-drying technique. This patent also describes a process of preparation of disodium salt of Ertapenem by dissolving crude product in water using NaHC03, followed by purification using column chromatography and subsequent lyophilisation.
US patent No. 6.504,027 provides a process for preparing Ertapenem in crystalline form which comprises deprotecting diprotected ertapenem using palladium on carbon and extracting a polar organic solution containing a crude mono-protected Ertapenem disodium salt with G4-10 alcohol in the presence of ion-pairing reagent followed by adjusting the pH to 5.5, collecting and crystallizing the resultant aqueous phase to produce Ertapenem disodium.

These processes are not attractive for industrial scale production because they involve chromatographic purification in certain stages for purification. Moreover, the palladium on carbon used for deprotection is 5-10% Pd/C. This high percentage of palladium leads to high content of palladium in final ertapenem. According to EMEA guidelines on permitted daily exposure (PDE) of metals, the PDE for parenteral route of administration is 10 μg/day whereas PDE for oral administration is 100 μg/day. Since ertapenem is administered through parenteral route, the high content of palladium in the product is highly unacceptable. Therefore, there is a need to develop a process which overcomes the mentioned drawbacks in prior art and minimises the palladium content in final product.
The present inventors have developed a process which is more practical, efficient, cost effective and which reduces the palladium content significantly to acceptable limit for parenteral administration.
SUMMARY OF THE INVENTION
Accordingly, the main aspect of the present invention is to provide a process for preparation Ertapenem monosodium comprising:
a) condensing the compound of formula II with compound of formula 111 in presence of a base and a solvent to obtain a monoprotected compound of formula IV or its sodium salt;
b) optionally isolating monoprotected compound of formula IV or its sodium salt;
c) deprotecting the monoprotected compound of formula IV or its sodium salt using palladium on carbon wherein percentage of palladium in palladium on carbon is in the range of 1 to 3; in a solvent in presence or absence of a buffer and in presence or absence of a sodium ion source; and
d) extracting the product with optional pH adjustment to obtain Ertapenem of formula I or its monosodium salt.
The above process is illustrated in below scheme:


DETAIL DESCRIPTION OF THE INVENTION
In an embodiment of the present invention, the protective group P selected from group such as allyl, 2,2,2,-trichloroethyl, 2-bromoethyl, benzhydryl, trityl, aryl, trimethylsilyl, triethylsilyl, 4-methoxybenzyl, t-butyl, p-nitrobenzyl and the like, preferably P is P-nitrobenzyl.
In another embodiment of the present invention, the solvent used in step (a) is selected from the group consisting of diethyl ether, tetrahydrofuran, toluene, xylene, dichloromethane, 1,2-dichloroethane, N,N-dimethyIformamide3 dimethylacetamide, N-methylpyrrolidinone, N-ethylpyrrolidtnone. N-methylpiperidinone, acetonitrile, propionitrile, and mixtures thereof, preferably N,N-dimethylformamide; and inorganic base used is selected from diisopropylethylamine (DIPEA), diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6-tetramethylpiperidine (TMP), 1,1,3,3-tetramethylguanidine (TMG), 1,8-diazabicyclo[4.3.0.]undec-7-ene (DBU) l,5-diazabicyclo[4.3.0]non-5-ene (DBN), N-methylpyrrolidine, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, disodium hydrogen phosphate, and the like preferably l,8-diazabicyclo[4.3.0.]undec-7-ene

(DBU). The condensation reaction may optionally contain bases like N,N-dimethylaminopyridine, N,N-diethylamino pyridine to avoid impurity formation. The condensed mass is further quenched to phosphoric acid to adjust the pH to 5 - 6 preferably 5.5 to 5.8.
In another embodiment of the present invention the monoprotected compound of formula (IV) can be isolated as an acid or a sodium salt, using mixture of ethyl acetate, alcohol and isopropyl ether or the solvent layer containing monoprotected ertapenem may be taken for deprotection without isolation.
In yet another embodiment of the present invention, the deprotection is preferably done by hydrogenolysis. The hydrogenolysis is usually done in presence of a metal catalyst, preferably in presence of hydrogen gas and palladium (Pd/C) catalyst where the percentage of palladium is in the range of 1 to 3 preferably 2.5 to yield Ertapenem monosodium. The standard process uses 5-10% palladium on carbon (Pd/C) for the said deprotection which results into upto 30ppm of palladium as a residue in the final product. This necessitates a purification step to reduce the residual palladium content in the product to a acceptable level. Whereas the present inventors found that when l%-3% preferably 2.5% Pd/C is used for hydrogenolysis, the residual Pd content in the final product is approx.0-3ppm. This obviates the necessity of purification step to reduce the residual Pd content. The solvent for deprotection in step (c) is selected from THF, acetonitrile, dioxane, ethyl acetate, isopropyl alcohol, n-propanol, methanol, dichloromethane, DMF, MDC, aqueous carbonic acid, water or mixtures thereof preferably aqueous MDC and n-propanol . The de-protection of protecting groups can be carried out using a mixture of solvents either in single phase or in biphasic medium. If required, the hydrogenation process can employ sodium ion source base such as sodium bicarbonate, sodium hydroxide, and sodium carbonate.
In yet another embodiment of the present invention, after completion of hydrogenation, the product was taken into aqueous medium, followed by optionally washing with organic solvents like MDC, butyl acetate, ethyl acetate, toluene, hexane, 1,2-dibromoethane and the like preferably MDC to remove reaction by-products and/or impurities. After hydrogenation, optionally carbon dioxide gas was purged to the reaction mass. The aqueous layer was subjected to degassing technique to remove the dissolved solvent if required. Further depending on the requirement, pH of aqueous layer optionally was adjusted using acid like acetic acid, formic acid, HC1, etc to obtain the compound of formula (I).
In yet another embodiment of the present invention, the pH of aqueous layer containing the Ertapenem monosodium was optionally reduced to 5 followed by quenching in to an alcohol, yielding crystalline ertapenem monosodium of formula (I).

In still further embodiment of the present invention, the starting material compound of formula (III) is prepared by utilizing technique known in the art.
Advantage of the process of the present invention:
a) The use of monoprotected intermediate of Ertapenem gives higher yield 0.5w/w to
0.6w/w as compared to 0.2w/w to 0.3w/w obtained in prior art.
b) Hydrogenation using MDC gives faster layer separation & adds to the yield
c) 2.5% Pd/C used for deprotection is not only cost effective but it also reduces the residual Pd content in the final ertapenem to an acceptable limit i.e 3 ppm. This obviates the necessity of purification step to reduce the residual Pd content in the final product.
d) The present process avoids hydrogenation work up as described in innovator patent.
e) Avoid consumption of more palladium carbon
The present invention is illustrated with the following non-limiting examples.
Example 1:
Step-I: Preparation of monoprotected Ertapenem monosodium
1 -Azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, 3-[(diphenoxyphosphinyl)oxy]-6-( 1 -hydroxyethyl)-4-methyl-7-oxo-,(4-nitrophenyl)methyl ester, [4R-[4a,5b,6b(R*)]] (MAP) (25 g) was taken in DMF(50 ml) and cooled to -40°C to -45°C. Ertapenem side chain -[(2S,4S)-4-Mercaptopyrrolidine-2-carboxamido]benzoic acid hydrochloride dissolved in DMF was added to above mixture at -40°C to -45°C. DBU (21 ml in 50 ml DMF) was added at the same temperature and stirred for I hr. After completion of the reaction, the reaction mass was quenched into phosphoric acid buffer in water (6 ml). The product was extracted by MDC and washed with water. The MDC layer containing monoprotected ertapenem was directly taken to next step for deprotection.
Step-II: Preparation of Ertapenem mono sodium
The MDC layer containing monoprotected ertapenem (250 g) obtained above was taken into a clean hydrogenater. DM water (250 ml) and sodium bicarbonate (3.5 gm) were added to it at 0°C to 5°C. 25gm of 2.5% Pd/C (50%wet) was charged into the hydrogenater and reaction was carried out under 6-12 kg hydrogen gas pressure for 3 hrs. After the completion of reaction, reaction mass was filtered and Pd/C bed was washed with DM water. Organic layer was separated. The aqueous layer was washed with MDC, treated with activated carbon, degassed and filtered. To the aqueous filtrate chilled methanol (160 ml) was added at -5°C to -10°C and chilled n-propanol (1300 ml) was added at -18°C to -20°C and stirred for 6 hrs. The precipitated mass was kept for 5 hours at -15°C to -20°C. The crystals were filtered

off under nitrogen and under vacuum at -10°C. The wet cake was washed with chilled ethanol and dried under Vacuum and nitrogen.
YIELD 7.5 to 9gm; M/C: NMT 15%

We claim:
1. A process for preparation Ertapenem monosodium of formula I comprising:

a) condensing the compound of formula II with compound of formula III in presence of a base and a solvent to obtain a monoprotected compound of formula IV or its sodium salt;

Where P is a protecting group b) optionally isolating monoprotected compound of formula IV or its sodium salt;


c) deprotecting the monoprotected compound of formula IV or its sodium salt using palladium on carbon wherein percentage of palladium in palladium on carbon is in the range of 1 to 3; in a solvent in presence or absence of a buffer and in presence or absence of a sodium ion source; and
d) extracting the product with optional pH adjustment to obtain Ertapenem of formula I or its monosodium salt.

2. A process for preparation of ertapenem monosodium according to claim 1 wherein, the percentage of palladium in Pd/C catalyst is 2.5%.
3. A process for preparation of ertapenem monosodium according to claim 1 wherein, the solvent for the deprotection in step (c) is selected from THF, acetonitrile, dioxane, ethyl acetate, isopropyl alcohol, n-propanol, methanol, dichloromethane, DMF, MDC, aqueous carbonic acid, water or mixtures thereof preferably aqueous MDC and n-propanol.
4. A process for preparation of ertapenem monosodium according to claim 1 wherein, the solvent for condensation in step (a) is selected from the group consisting of diethyl ether, tetrahydrofuran, toluene, xylene, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, N-ethylpyrrolidinone, N-methylpiperidinone, acetonitrile, propionitrile, and mixtures thereof, preferably N,N-dimethylformamide;
5. A process for preparation of ertapenem monosodium according to claim 1 wherein, the base for condensation in step (a) is selected from the group consisting of diisopropylethylamine (D1PEA), diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6-tetramethylpiperidine (IMP), 1,1,3,3-tetramethylguanidine (TMG), l,8-diazabicyclo[4.3.0.]undec-7-ene (DBU) l,5-diazabicyclo[4.3.0]non-5-ene (DBN), N-methylpyrrolidine, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, disodium hydrogen phosphate, and the like preferably 1,8-diazabicyclo[4.3.0.]undec-7-ene(DBU).