IMPROVED PROCESS FOR THE PREPARATION OF CEFEPIME

INTERMEDIATE

Field of the Invention

The present invention provides an improved process for the preparation of the compound of formula (I).

wherein HX represents HI, HCl, H ₂ SO ₄ and the like. The compound of formula (I) is an important intermediate in the preparation of Cefepime or its salts.

Background of the Invention

Cefepime is chemically known as [6R-[6α, 7β(Z)]]-l-[7-[(2-amino-4- thiazolyl)(methoxyimino)acetylamino]-2-carboxy-8-oxo-5-thia- l-azabicyclo [4.2.0]oct-2-en-3-ylmethyl]-l-methylpyrrolidinium hydroxide inner salt or (6R,7R)-7- [2-(2-aminothiazol-4-yl)-2(Z)-(methoxyimino)acetamido]-3-(l- methylpyrrolidiniornethyl)-3-cephem-4-carboxylate. Cefepime is the fourth- generation cephalosporin that is active against a wide range of gram-positive and gram-negative aerobic organisms and is disclosed in US Patent No. 4,406,899. According to this patent Cefepime is prepared by the following process:

US patent No. 4,868,294 claims a process for the preparation of stable, crystalline 7-amino-3-[(l -methyl- l-pyrrolidinio)methyl] ceph-3-em-4-carboxylate salts substantially free of the δ ² isomer starting from 7-aminocephalosporanic acid (7- ACA) in 1,1,2-trichlorotrifluoroethane (Freon TF) or 1,1,1-trichlorotrifluoroethane as the solvent as shown below :

US patent No. 5,594,131 claims almost a similar process for the preparation of stable, crystalline 7-amino-3-[(l -methyl- l-pyrrolidinio)methyl]ceph-3-em-4- carboxylate salts substantially free of the δ ² isomer by utilizing Cs _-8 cycloalkanes as solvent.

WO 2006/075244 (Application No: IN 27/CHE/2005) discloses the preparation of compound of formula (I) using decalin, tetralin, hexane, cyclohexane and petroleum ether as solvent systems.

In WO 2008/010042 (Application Number IN 1246/CHE/2006), the applicant has disclosed a process for the preparation of compound of formula (I) using n- heptane, n-octane or mixtures thereof. During our continued search we have identified a process, which yield the compound of formula (I) in good purity, which is substantially free from δ ² isomer and useful in the preparation of Cefepime. The present invention identifies the dual role of hexamethyldisilane as a solvent and reagent.

Objective of the Invention

The main objective of the present invention is to provide a process for the preparation of compound of formula (I) in good purity, which is substantially free from δ ² isomer.

Another objective of the present invention is to provide a process for the preparation of intermediate of formula (I), which is easy to implement on commercial scale, and avoids solvents like cyclohexane, dichloromethane (MDC), and decalin.

Summary of the Invention

Accordingly, the present invention provide a process for the preparation of compound of formula (I)

(I) which comprises the steps of: i) preparing "solution A" by reacting N-methylpyrrolidine of formula (IV)

(NMP) with iodine in hexamethyldisilane (HMD), ii) preparing "solution B" by reacting 7-ACA of formula (II) with silylating agent in hexamethyldisilane (HMD), iii) condensing "solution A" with "solution B" to produce compound of formula

(VI), and iv) treating the compound of formula (VI) with aqueous alcoholic solvent or alcoholic solvent or water and isolating the compound of formula (I). The process is shown in Scheme-2

(I)

Scheme-2

Detailed description of the invention

In an embodiment of the present invention silylating agent used in step (ii) is selected from hexamethyldisilazane (HMDS), trimethylchlorosilaneOTMCS), trimethylsilyl iodide (TMSI), N,O-bis-(trimethylsilyl)-acetamide (BSA), methyltrimethylsilyltrifluoroacetamide (MSTFA), N,O-bis-

(trimethylsilyl)trifluoroacetamide (BSTFA) or mixtures there of.

In another embodiment, the present invention makes use of hexamethyldisilane as a solvent system for carrying out the reaction, the use of which has been found to have advantages over the conventional solvent system. None of the prior art hitherto suggests or motivates the use of hexamethyldisilane as a solvent system. Accordingly, the use of hexamethyldisilane as a solvent system constitutes the novelty of the present invention. The conventional solvent system requires cumbersome solvent recovery process. The use of hexamethyldisilane obviates such problems and the recovery of hexamethydisilane is found to be good over the cycloalkane as the use of hexamethyldisilane yields good quality as well as quantity of final compound, and hence industrially advantageous. Apart from these advantages, cycloalkanes like cyclohexane, methyl cyclopentane becomes a peroxide hazard if concentrated, through distillation or evaporation as mentioned in Jackson, J.

Chem. Ed., 1970. Since, industrial process prefers recovery of solvent system, the present invention prefers such advantage. Accordingly, the present invention provides a novel solvent system that avoids the drawbacks associated with the processes reported in the prior art. Thus, the present invention identifies the dual role of hexamethyldisilane as a solvent system and reagent.

In still another embodiment of the present invention iodotrimethylsilane is prepared by reacting hexamethyldisilane (HMD) with iodine at a temperature in the range of 10 ⁰ C to 100 ⁰ C. To this solution NMP was added to yield "solution B."

In yet another embodiment of the present invention isolation of compound of formula (I) is carried out by reacting the compound of formula (VI) obtained in step (iii) with water or lower alkanol or aqueous lower alkanol such as methanol, isopropyl alcohol, butanol and the like.

In one more embodiment of the present invention the compound of formula (I) can be prepared by reacting silylated 7-ACA of formula (II) with N-methylpyrrolidine of formula (IV) in hexamethyldisilane as a solvent system, to produce compound of formula (VI), followed by removing the silyl protecting group of formula (VI).

In still another embodiment of the present invention the compound of formula (I) can be prepared by utilizing the following scheme.

(VII)

In yet another embodiment of the present invention, the compound of formula (VII) is prepared by reacting silylated 7-ACA of formula (III) with iodotrimethylsilane in hexamethyldisilane.

In yet another embodiment of the present invention the compound of formula

(I) further converted to cefepime dihydrochloride monohydrate by the conventional method or by the method disclosed in our co-pending application No. 673/CHE/2003, 780/MAS/2002, 1020/CHENP/03, or 848/MAS/2002

The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.

Example 1 (όRJRW-Amino-S-IQ-methyl-l-pyrrolidino^methyllceph-S-eπM-e arboxylate hydroiodide salt.

Solution A:

A suspension of iodine [88.5 g] in hexamethyldisilane was heated to 60-70 ⁰ C under nitrogen atmosphere and maintained for 3-6 hours. The above solution was cooled to O ⁰ C and added N-methylpyrrolidine (26 g) in hexamethyldisilane (25 mL).

The resultant slurry was stirred at 0-15 ⁰ C for 30 minutes.

Solution B:

To a suspension of 7-ACA (50 g) in hexamethyldisilane (150 mL) was added

BSA (78 g) at 10-30 ⁰ C. The resulting mixture was stirred for 1-3 hours under nitrogen atmosphere.

Condensation:

The silylated 7-ACA solution [Solution B] was added to the Solution A at O ⁰ C.

The suspension was heated to 30-50 ⁰ C and maintained till completion of reaction.

After the completion of the reaction, reaction mixture was cooled to 3-5 ⁰ C. Cold aqueous methanol (50%) was added at 5-10 ⁰ C followed by concentrated hydrochloric acid. The aqueous phase was separated and combined with the aqueous methanol extract of the organic phase. To the aqueous phase, methanol and activated carbon were added, stirred and filtered. The filtrate was diluted with aqueous methanol. The product was crystallized by adjusting the pH using triethylamine at 15-2O ⁰ C. The

crystallized product was filtered and washed with cold aqueous methanol (10%) followed by cold methanol. Drying under vacuum at 35 -4O ⁰ C afforded pure title compound.

Example 2 f6R,7R)-7-Amino-3-[(l-methyl-l-pyrroIidino)methyllceph-3-em- 4-carboxylate hydroiodide salt- Solution A:

A suspension of iodine [88.5g] in hexamethyldisilane at 20-30 ⁰ C was heated to 60-70 ⁰ C under nitrogen atmosphere and maintained for 3-6 hours. The above solution was cooled to O ⁰ C and added N-methylpyrrolidine in hexamethyldisilane.

The resultant slurry was stirred at 0-15 ⁰ C for 30 minutes.

Solution B:

To a suspension of 7-ACA (50 g) in hexamethyldisilane was added BSA (78 g) at 10-30 ⁰ C. The resulting mixture was stirred for 1-3 hours under nitrogen atmosphere.

Condensation:

The silylated 7-ACA solution [Solution B] was added to the Solution A at O ⁰ C.

The suspension was heated to 30-50 ⁰ C and maintained till completion of reaction.

After the completion of the reaction, reaction mixture was cooled to 3-5 ⁰ C. Cold aqueous methanol (50%) was added into the reaction mixture followed by concentrated hydrochloric acid. The aqueous phase was separated and combined with aqueous methanol extract of the organic phase. To the aqueous phase, methanol and activated carbon were added, stirred and filtered. The filtrate was diluted with aqueous methanol. The product was crystallized by adjusting the pH to 3.0 - 3.5 using triethylamine. The crystallized product was filtered and washed with cold aqueous methanol followed by cold methanol. Drying under vacuum at 35 -4O ⁰ C afforded pure title compound.