WO2008041100A1

WO2008041100A1 - Improved process for the preparation of cephalosporin antibiotics

Info

Publication number: WO2008041100A1
Application number: PCT/IB2007/002917
Authority: WO
Inventors: Palanisamy Senthilkumar Udayampalayam; Sundaravadivelan Sivakumaran; Prabhat Kumar Sahoo
Original assignee: Orchid Chemicals & Pharmaceuticals Limited
Priority date: 2006-10-04
Filing date: 2007-10-03
Publication date: 2008-04-10

Abstract

Abstract The present invention more particularly relates to a process for the preparation of cephalosporin antibiotics of the Formula (I) wherein R1 represents hydrogen, trityl, alkyl like CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6) alkyl; R2 is carboxylate ion or COORd, where Rd represents hydrogen, ester or a counter ion which forms a salt; R3 represents hydrogen, CH3, CH2OCH3, CH2OCOCH3, CH=CH2, Formula (II).

Description

IMPROVED PROCESS FOR THE PREPARATION OF CEPHALOSPORIN

ANTIBIOTICS

Field of the Invention

This specification is a patent of addition to our co-pending application 560/CHE/2005 filed on 12.05.2005. The present invention relates to an improved process for the preparation of cephalosporin antibiotics, which have a wide range of anti-bacterial activity. More particularly, the present invention relates to a process for the preparation of cephalosporin antibiotic of the formula (I)

OR₁

wherein Ri represents hydrogen, trityl, CH₃, CR₃R_bCOOR_c where R₃ and R_b independently represent hydrogen or methyl and R₀ represents hydrogen or (C _r C₆) alkyl; R₂ is carboxylate ion or COOR_d, where R^ represents hydrogen, ester or a counter ion which forms a salt; R₃ represents hydrogen, CH₃, CH₂OCH₃, CH₂OCOCH₃, CH=CH₂,

HN-N.

/^v s.

Background of the Invention

US patent Nos. 4,767,852 and 5,003,073 disclose a process for the production of cephalosporin derivatives by acylating 7-amino-3-cephem-4- carboxylic acid derivative with 2-mercaptobenzothiazolyl-(Z)-2-(2- aminothiazol-4-yl)-2-methoxyimino acetate of the formula (II) (MAEM),

using solvents such as chlorinated hydrocarbons, ethers or esters such as ethyl acetate or in a mixture of such solvent with water.

US patent 5,026,843 discloses a process for preparing ceftriaxone disodium comprising reacting 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5- oxo-l^^-triazin-S-ytythioJmethylJ-S-cephem^-carboxylic acid with 2- mercaptobenzothiazolyl 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetate in an aqueous solution in suitable solvents, in the presence of an amine and the obtained aqueous solution is treated with a base selected from the group consisting of dicyclohexylamine, diphenylamine, diisopropylamine, N-tert- butylcyclohexylamine and N,N-dibenzylethylenediamine. This patent discloses the use of THF/water for the condensation. Moreover, the complexity in workups involving THF/water is solved by adding another solvent like ethyl acetate, methylene chloride etc., for extraction and subsequent isolation of the product as either the acid or its salts. US patent number 5,574,154 discloses and claims a process for the preparation of the different cephalosporin derivatives by the condensation of MAEM with different cephem moieties in the presence of a solvent and a base. The solvent used for the condensation is selected from acetone, acetonitrile, carbon tetrachloride, methylene chloride, toluene, methanol, ethanol, iso- propanol, dioxane, iso-propyl ether, N-methyl pyrrolidone and dimethyl formamide (DMF) and the base used is triethylamine.

WO 00/68234 discloses a process for the preparation of cefpodoxime acid, comprising condensation of 7-amino-3-methoxymethyl-3-cephem-4- carboxylic acid with MAEM in the presence of an organic solvent and an organic base and optionally in the presence of water.

US 5,527,906 describes a process for the preparation of Ceftriaxone disodium hemiheptahydrate involving condensation of 7-amino-3-{[(2,5- dihydro-2-methyl-6-hydroxy-5-oxo-as-triazin-3-yl)thio]methyl}-cephem-4- carboxylic acid derivative with MAEM using NaHCO₃ in aqueous acetone. Even though this patent motivates the direct isolation of sodium salt of cephalosporin after acylation or condensation reaction, this patent yields a product in which the sodium content in final product is not consistent, as it utilizes the inorganic base for condensation.

US 5,574,155 describes a process for the preparation of Ceftriaxone disodium hemiheptahydrate by condensing 7-amino-3-{[(2,5-dihydro-6- hydroxy-2-methyl-5-oxo-l,2,4-triazin-3-yl)thio] methyl }-3-cephem-4-carboxylic acid (7-ACT) with MAEM using aqueous acetone in the presence of an organic base that does not contain sodium ions. According to this process, workup is required before adding sodium ion source.

IN 784/MAS/2002, discloses a process in which condensation was carried out in THF/water, followed by addition of ethyl acetate to the removal of by- products. Though this process affords good quality product, it is associated with problems like solvent recovery.

Even though many prior art report methods for the preparation of compound of formula (I), each process has some limitation with respect to color, quality, yield or residual solvent content in the final API. Hence in view of the commercial importance of compound of formula (I) there remains a need for a better process.

During the course of our research efforts to develop an easily scalable and commercially viable process for the preparation of cephalosporins, we have observed that the use of aqueous solvents like acetone, THF in the presence of sodium-2-ethyl hexanoate gives high yields and the process is easy to handle in the large scale operations

Unexpectedly it was observed that, this condensation i.e acylation of 7- cephem moiety and salification could be achieved using single base in single solvent. This invention is ecofriendly, cost effective, high yielding and easy to scale up with very less unit operations. None of the prior art suggests the use of sodium 2- ethyl hexanoate as a base during the course of acylation and teaches the technique of isolating the final API by the addition of water to remove the by-products and also the technique of isolating the final API as sodium salt by the addition of water miscible solvent.

Objectives of the Invention

The primary objective of the invention is to provide a process for the preparation of cephalosporin antibiotics of the general formula (I), which is simple, high yielding and cost effective.

Another objective of the present invention is to provide a process for the preparation of number of cephalosporin antibiotics, in which the by-products are removed and the same can be recycled using simple & industrially viable technique.

Summary of the Invention

Accordingly, the present invention provides a process for the preparation of cephalosporin antibiotics of the formula (I)

wherein Ri represents hydrogen, trityl, alkyl like CH₃, CR₃R_bCOOR₀ where R₃ and R_b independently represent hydrogen or methyl and R₀ represents hydrogen or (Ci-C₆) alkyl; R₂ is carboxylate ion or COOR_J, where Rj represents hydrogen, ester or a counter ion which forms a salt; R₃ represents hydrogen, CH₃, CH₂OCH₃, CH₂OCOCH₃, CH=CH₂,

HN-N W,

/^v N

which comprises the steps of: (i) condensing the compound of the formula (II) wherein R₁ is as defined above with 7-amino cephem derivative of the formula (III) wherein R₂ and R₃ are as defined above; using sodium-2- ethyl hexanoate or sodium acetate in the presence of water and in the presence or absence of water miscible organic solvent, wherein the improvement consists of the usage of sodium-2-ethyl hexanoate or sodium acetate,

(ii) adding water or acetone to the step (i) mass, (iii) optionally filtering the by-product, and (iv) isolating the compound of formula (I).

The process is shown in Scheme- 1

(H) (III)

_/OR,

Scheme- 1 Detailed Description of the Invention

In an embodiment of the present invention the water miscible organic solvent used in step (i) is selected from acetone, tetrahydrofuran (THF), acetonitrile, Isopropyl alcohol or mixtures thereof.

In another embodiment of the present invention condensation reaction is carried out in aqueous solvent, wherein the water to solvent ratio varies from 0% to 100%, preferably 30% to 70%.

In still another embodiment of the present invention the compound of formula (I) is isolated from the reaction mass as sodium salt if required by the addition of excess acetone.

In one more embodiment of the present invention the compound of formula (I) is isolated from the reaction mass as acid (R₂ is COOH) by the addition of water. During the process of water addition, the by-product 2- mercaptobenzothiazole (MBT) is precipitated; accordingly the present invention provides a simple technique of recovering the MBT. The compound of formula (I) is isolated from the reaction mass by adjusting the pH. Surprisingly the compound thus isolated does not contain any detectable limit of MBT, whereas the literature processes yields the compound of formula (I) that contains the said MBT as an impurity. Owing to the toxic nature of MBT, the presence of MBT in the final API is not advisable in terms of pharmacopoeia requirement. Since the present invention obviates the problem associated with prior art process, it is economically and industrially viable.

In yet another embodiment of the present invention, the use of conjugate base of an organic acid like sodium 2-ethyl hexonate or sodium acetate obviates the use of organic amine during condensation step and hence provides a process to isolate the sodium salt directly. One of the problems associated with acylation or condensation stage is degradation of final API and the degradation is directly associated with the basicity of the base used. The use of inorganic base like sodium carbonate or strong organic bases like sodium methoxide is not advisable, as they tend to degrade the final API. Because of the less basic nature of sodium 2-ethyl hexanoate, the degradation of the final API is minimized and it also provides direct isolation of sodium salt. Hence the process of the present invention is commercially more viable over the existing prior art processes.

In yet another embodiment of the present invention the compound of formula (I) obtained is a syn-isomer.

In still another embodiment of the present invention the starting material, 7-amino cephem derivative of formula (III) is prepared by utilizing the technique known in the prior art.

In one more embodiment of the present invention, the commercially important cephalosporin compounds of formula (I) that can be manufactured by the process of this invention includes Cefetamet, Cefotaxime, Cefditoren, Ceftizoxime, Cefepime, Ceftriaxone, Cefixime, Cefdinir, Cefquinome, Cefpodoxime, Cefteram, Cefoselis, Cefuzonam and the like or its sodium salt or its hydrated form of sodium salt. If required the compound of formula (I) is converted into its pharmaceutically acceptable salt or ester by utilizing the process known in prior art. It may be noted that the de-protection of protecting groups (in Rl group) in compound of formula (I) obtained according to the invention was optionally required to yield the final Cephalosporin compounds of formula (I) of the present invention, and the said de-protection is done by utilizing the technique known in prior art.

In yet another embodiment of the present invention the compound of formula (I) or its solvates or its salt can be formulated by conventional method. Accordingly the conventional formulation to the invention there is provided a stable parenteral aqueous solution comprising pharmaceutically acceptable β- lactam antibiotic, and/or EDTA, and/or sodium citrate, which is preferably suitable for intramuscular and intravenous administration.

The following examples are provided by way of illustration only and should not be construed to limit the scope of the invention.

Example 1

Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3- methyl- ceph-3-em-4-carboxylic acid (Cefetamet sodium) To a mixture of water (250 rnL) and acetone (500 mL), 7-Amino desacetoxy cephalosporanic acid (50 g) and 2-mercaptobenzothiazolyl (Z)-2-(2- aminothiazol-4-yl)-2-methoxyimino acetate (90 g) (MAEM) were added at 5- 10⁰C. It was followed by addition of sodium 2-ethylhexanoate (77.0 g) in one lot and stirred till completion of reaction. After completion of reaction, further acetone was added (3L) and the precipitated solid was filtered under nitrogen atmosphere and washed with acetone (500 mL) and dried to give 95 g of Cefetamet sodium of 99 % purity.

The cefetamet sodium thus obtained is converted to Cefetamet pivoxil as follows; Preparation of Cefetamet Pivoxil

To DMF (25OmL), Cefetamet Sodium (10Og) was added at room temperature and stirred to get clear solution. To the clear solution, solid sodium bicarbonate (1.6g) was added. The reaction mass was cooled to -25 to -30⁰C and iodomethyl pivalate (45.83g) was added in one lot and stirred for 2 h. The reaction mixture was poured into a mixture of ethyl acetate (50OmL) and water (50OmL). Sodium thiosulphate and EDTA were added into this and the mixture was stirred followed by pH adjustment with the dilute HCl. The layers were separated and the organic layer was washed with brine solution. The organic layer was charcolised and filtered, the carbon bed was washed with ethyl acetate. The ethyl acetate layer was poured into isopropyl ether (2.5L). The solid obtained was stirred at 5°C, filtered, washed with IPE and finally dried to get the title compound. Purity (HPLC): 99% Yield 70-80 g.

Advantages: 1. Using the process according to the invention, the desired sodium salt of

Cephalosporin antibiotic is prepared directly.

2. The product is isolated from the reaction mixture directly in highly pure form and high yield.

3. The present invention is eco-friendly and economical as product isolation is very simple.

4. Unit operation is less and hence advantageous from operational point of view in plant.

5. Degradation of final API is minimized.

Example 2

7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamidol-3methyl- ceph-3- eni-4-carboxyIic acid (Cefetamet)

To a mixture of water (200 mL) and acetone (500 mL), 7-Amino desacetoxy cephalosporanic acid (100 g) and 2-mercaptobenzothiazolyl (Z)-2-(2- aminothiazol-4-yl)-2-methoxyimino acetate (180 g) (MAEM) were added at 5-

10⁰C. It was followed by addition of sodium 2-ethylhexanoate (1 17.0g) in one lot and stirred till completion of reaction. After completion of reaction, further water was added (180OmL) and the precipitated by-product (mercapto benzothaizole & MAEM) was filtered. The pH of clear filtrate was adjusted to

2.5 - 3.0 at 5°C. The solid obtained was filtered, washed with aqueous acetone and dried to yield cefetamet acid in pure form (165 g; purity: 98.6%) Advantages:

(i) Using the process according to the invention, the desired cephalosporin antibiotic is prepared directly, and the same is free from by-product MBT & and unreacted MAEM.

(ii) IN 784/MAS/2002, discloses a process in which the said process involves the use of ethyl acetate to remove the byproduct, leading to complications in the recovery of solvent.

(iii) Though the use of excess acetone yields the final API in good quality, the removal of by-product from the filtrate and the recovery of solvent make the invention industrially and economically not viable.

(iv) The product is isolated from the reaction mixture directly in highly pure form and high yield.

(v) The present invention is eco-friendly and economical as product isolation is very simple.

(vi) Unit operation is less and hence advantageous from operational point of view in plant.

(vϋ) Degradation of final API is minimized, due to the usage of sodium-2-ethyl hexanoate and sodium acetate.

(viϋ) Use of acetone or other solvent is minimized and the process is environment friendly (Green Chemistry).

(ix) The by-product (MBT) is isolated from the reaction mass in almost pure form, which can be further, purified or converted into bis-benzothiazole di-sulfide and can be reused.

Example - 3

Preparation of 7-[[(Z)-2-(2-aminothiazol-4-yl)-2-methoxy imino]acetamido]-3-H(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-l,2,4- triazin-3-yl) thio] methyl]-3-cephem-4-carboxylic acid

(Ceftriaxone): 7-Amino-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-l,2,4-triazin- 3yl)thio]methyl]3-cephem-4-carboxylic acid (50 g) and 2-mercapto- benzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate (51.9 g) (MAEM) were taken in water (100 mL) /THF (250 mL) mixture and cooled to 0 °C. Sodium-2-ethyl hexanoate (44.7 g) was added to the mixture and stirred at 0 to 5 ⁰C. After completion of the reaction, water (1000 mL) was added to the reaction mixture and the precipitated by-product (2-mercaptobenzothaizole (MBT) & MAEM) was filtered. The pH of clear filtrate was adjusted to 2.5 - 3.0 at 5°C. The solid obtained was filtered, washed with aqueous acetone and dried to yield Ceftriaxone acid in pure form.

Example - 4

Preparation of 3-AcetyIoxymethyl-7-[(Z)-(2-aminothiazoIyI-4-yl)-2-

(methoxyimino)acetamido]-3-cephem-4-carboxylic acid (Cefotaxime acid):

7-Amino cephalosporanic acid (50 g) and 2-mercapto-benzothiazolyl- (Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate (MAEM) (70.8g) were taken in a mixture of acetonitrile (250 mL)/water (100 mL). Sodium-2-ethyl hexanoate (61 g) was added to the mixture and stirred at 6 to 8 ⁰C for 12 hrs. After completion of the reaction, water (1000 mL) was added to the reaction mixture and the precipitated by-product (2- mercaptobenzothaizole (MBT & MAEM) was filtered. The pH of clear filtrate was adjusted to 2.5 - 3.0 at 5°C. The solid obtained was filtered, washed with aqueous acetone and dried to yield title compound.

Reference Example-1: Preparation of Ceftazidime

(6R,7R)-7-[[2-(2-amino-4-thiazoIyl)-(Z)-2-(tert.butoxycarbonyl-l- methylethoxy)imino]acetamido]-3-(l-pyridiniummethyl)-3-cephem- 4-carboxylate (ceftazidime intermediate) 19.1 g of 2-(2-amino-4-thiazolyl)-(Z)-2-[(l-tert.butoxycarbonyl-l- methylethoxy)imino]thioacetic acid-S-benzothiazol-2-yl-ester, 14.6 g of (6R,7R)-7-amino-3-(l-pyridiniummethyl)-3-cephem-4-carboxylic acid iodide, monohydrate and 5.6 ml of triethylamine were stirred for 24 hours at 0° C in a mixture of 142.5 ml of dichloromethane and 7.5 ml of methanol. The solid substance was filtered off, washed with dichloromethane and vacuum-dried at room temperature. 16.0 g of the title compound were obtained in crystalline form. This compound was optionally stirred with acetone followed by filtration yield to get pure (6R,7R)-7-[[2-(2-amino-4-thiazolyl)-(Z)-2-(tert.butoxycarbonyl-l- methylethoxy)imino]acetamido]-3-(l-pyridiniummethyl)-3-cephem-4- carboxylate. This compound thus obtained was treated with HCL in formic acid at 25° C for two hrs. After the completion of the reaction, ethyl acetate was added to the reaction mass and the layers were separated. The aqueous layer was treated with Amberlite resin to adjust the pH to 4.0. The product was filtered, slurry washed with acetone and dried to get Ceftazidime pentahydrate in pure form.

Claims

We claim:

1. A process for the preparation of cephalosporin antibiotics of the formula (I)

wherein R_x represents hydrogen, trityl, CH₃, CR₃R_bCOOR_c where R_a and R_b independently represent hydrogen or methyl and R₀ represents hydrogen or (Ci-C₆) alkyl; R₂ is carboxylate ion or COORj, where Rj represents a counter ion which forms a salt; R₃ represents hydrogen, CH₃₅ CH₂OCOCH₃, CH=CH₂,

which comprises the steps of

(i) condensing the compound of the formula (II)

wherein R₁ is as defined above with 7-amino cephem derivatives of the formula (III)

(III) wherein R₂ and R3 are as defined above using a conjugate base of an organic acid in water and in the presence or absence of water miscible solvent selected from the group consisting of acetone, THF, acetonitrile, isopropyl alcohol to produce a compound of formula (I) where all symbols are as defined above, wherein the improvement consists of the usage of sodium-2-ethylhexonate or sodium acetate,

(ii) adding water or acetone to the step (i) mass,

(iii) optionally filtering the by product, and

(iv) isolating the compound of formula (I).

2. A process for the preparation of cephalosporin antibiotics of the formula (I)

wherein R₁ represents hydrogen, trityl, CH₃, CR₃R_bCOOR_c where R₃ and R_b independently represent hydrogen or methyl and R₀ represents hydrogen or (Ci-C₆) alkyl; R₂ is carboxylate ion or COOR_d, where R_<j represents a counter ion which forms a salt; R₃ represents hydrogen, CH₃, CH₂OCOCH₃, CH=CH₂,

which comprises the steps of

(i) condensing the compound of the formula (II)

wherein R₁ is as defuied above with 7-amino cephem derivatives of the formula (III)

(III) wherein R2 and R3 are as defined above using a conjugate base of an organic acid in water and in the presence or absence of water miscible solvent selected from the group consisting of acetone, THF, acetonitrile, isopropyl alcohol to produce a compound of formula (I) where all symbols are as defined above, wherein the improvement consists of the usage of sodium-2-ethylhexonate or sodium acetate, (ii) adding water to the step (i) mass, (iii) filtering the by product, and

(iv) isolating the compound of formula (I).

3. A process according to Claim 1, wherein the compound of formula (I) is any one of i) 7- [ (Z)-2- (2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-

3-cephem-4- carboxylic acid i. e. (cefdinir), ii) 7- [ (Z)-2- (2-amino-4-thiazolyl)-2-methoxyimino) acetyl] ainino-3- [

(lZ)-2- (4- methyl-5-thiazolyl) ethenyl-3-cephem-4-carboxylic acid,

(cefditoren) or its ester like cefditoren pivoxil, iii) 7- [ (Z)-2- (2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3- (I- methylpyrrrolodino) methyl-3-cephem-4-carboxyIate i. e. (cefepime), iv) 7- [ (Z)-2- (2-aminothiazol-4-yl) methoxyiminoacetamido]-3-methyl-

3-cephem-4- carboxylic acid (cefetamet), or its ester like cefetamet pivoxil, v) 7- [ (Z)-2- (2-aminothiazol-4-yl)-2-carboxymethoxyimino acetamido]

-3-vinyl- 3-cephem-4-carboxylic acid (cefixime), vi) 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[ 1 - methyl- lH-tetrazol-S-yIJthioJmethyll-S-cepherrM-carboxylic acid i.e. cefmenoxime, vii) 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[[5- carboxymethyl)-4-methyl-2-thiazolyl] thio] methyl]- 3-cephem-4- carboxylic acid (cefodizime), viii) 7-[(Z)-2- (2-aminothiazol-4-yl)-2-methoxyiminoacetamido] cephalosporanic acid (cefotaxime), ix) 7- [ (Z)-2- (2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3- [92,

3- cyclopenteno-1-pyridinium) methyl]- 3-cephem-4-carboxylic acid

(cefpirome), x) 7- [ (Z)-2- (2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3- methoxymethyl-3-cephem-4-carboxylate-(cefpodoxime) or its ester like cefpodoxime proxetil, xi) 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[l- azabicyclo [4.2. 0] oct-2-en-3-yl] methyl-5,6, 7- tetrahydroquinolinium-4- carboxylic acid inner salt i. e. cefquinome, xii) 7- [(Z)-2- (2-aminothiazol-4-yl)-2- (1-carboxy-l- methylethyl) oximinoacetamido}-3-[pyridinium] methyl-3-cephem-4- carboxylacid acid inner salt (ceftazidime), xiii) 7- [ (Z)-2- (2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3- [2-

(5-methyl- 1, 2,3, 4-tetrazoyl)-methyl-3- cephem-4-carboxylic acid

(cefteram). xiv) 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[(2- furanylcarbonyl) thio] methyl]- 3-cephem-4-carboxylic acid

(ceftiofur), xv) 7- [ (Z)-2- (2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3- cephem-4- carboxylic acid (Ceftizoxime), xvi) 7-[[(Z)-2-(2-Aminothiazol-4-yl)-2-methoxy imino]acetamido]-3-

[[(2,5-dihydro-6-hydroxy-2-methy 1-5-oxo- l,2,4-triazin-3- yl)thio]methyl]-3-cephem-4-carboxylic acid (Ceftriaxone).