WO2007083187A2

WO2007083187A2 - An improved process for the preparation of monobactam antibiotic

Info

Publication number: WO2007083187A2
Application number: PCT/IB2006/003783
Authority: WO
Inventors: Udayampalayam Palanisamy Senthilkumar; Jitendra Bhagwandas Kevat; Andrew Gnanaprakasam; Chinnian Jeyaraman Magesh; Manohar Puppala; Venugopal Sivasankaran
Original assignee: Orchid Chemicals & Pharmaceuticals Limited
Priority date: 2006-01-16
Filing date: 2006-12-28
Publication date: 2007-07-26
Also published as: WO2007083187A3

Abstract

The present invention relates to the process for the preparation of monobactam antibiotic of formula (I). More particularly, the present invention relates to the preparation of Aztreonam of formula (I) from its precursor, tertiary butyl ester of Aztreonam of formula (II).

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF MONOBACTAM ANTIBIOTIC

Field of the Invention

Background of the Invention

Aztreonam is chemically known as (Z)-2-[[[(2-amino-4-thiazolyl)[[(2S,3S)- 2-methyl-4-oxo-l-sulfo-3-azetidinyl]carbamoyl]methylene]amino]oxy]-2-

C0NFIRMAT10N COPY methylpropionic acid. Aztreonam is the only clinically available member of a unique class of beta-lactam antibiotics called 'monobactams'.

Monobactam such as Aztreonam is said to exhibit potential antibacterial properties against gram positive and gram negative bacteria. The antibacterial properties of compound such as Aztreonam is due to the presence of sulfonic acid substituent in 1 -position of the beta lactam nucleus and acyl amino substitutent in the 3-position of the beta lactam nucleus. Owing to these properties, aztreonam is widely used in the treatment of bacterial infections such as urinary tract and respiratory infections.

Aztreonam is originally disclosed in US patent 4,775,670. Several patent/publications disclose various process for preparing Aztreonam. One of the general process widely followed is depicted in scheme (I) as given below.

(I) In the above scheme the de-protection of t-butyl ester in compound of formula (II) is the crucial step, which determines yield and purity. As discussed below several patent/publications are disclosing various reagents for this hydrolysis of t-butyl ester.

US patent 4,775,670 involves use of TFA/anisole for the de-protection of compound of formula (II). Since TFA is a hazardous solvent, it is not suitable from manufacturing point of view. Also the final API contains TFA as a residual solvent.

US 4,946,838 patent discloses a process for the preparation of β-form of aztreonam which is crystalline, anhydrous and substantially non-hygroscopic form which involves treating diphenyl methyl ester of Aztreonam with trifluroacetic acid in the presence of anisole under anhydrous conditions to produce α-form which is then subjected to recrystallization to give β-form.

US 4,652,651 discloses that the process of preparing aztreonam involving de- protection of tertiary butyl ester of aztreonam and the said process of de-protection is facilitated by treating tertiary butyl ester of aztreonam with trifluroacetic acid, concentrated hydrochloric acid (37%) and p-toluenesulphonic acid at lower temperature from -10°C to room temperature.

WO 2004/013133 discloses the process for the preparation of Aztreonam by reacting [3S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)[(l-t-butoxycarbonyl-l- methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-l-azetidinesulfonic acid with an aqueous acid at elevated temperature. The aqueous acid is preferably mineral acid, such as hydrochloric acid, sulfuric acid and trifluroacetic acid. The aqueous acid is 1 :1 v/v HCl: water mixture. The hydrolysis is carried out at elevated temperatures, preferably between 50⁰C and 8O⁰C.

US 2005/0014739 claims crystalline, anhydrous β-form of Aztreonam having less than 2.5% by weight residual solvent. On the contrary, while analyzing the innovator's marketing sample, it has been found that it contains 1 % of residual solvent or even less than 0.5% residual solvent. Similar to the teaching given in Example 3 of US 4,946,838, where base was utilized for dissolution at room temperature, WO 2003/018578 teaches the dissolution of oc-form of aztreonam at - 10⁰C to +15⁰C, and this publication also claims a process for the preparation of said β-form in Claim 4, the said process comprises the steps of (a) dissolving oc-form of aztreonam in an organic solvent at a temperature at -60⁰C to 5°C in the presence of base to form clear solution (b) adding acid to the solution formed in (a); (c) stirring the solution efficiently and (d) recovering the β-form of Aztreonam. When we repeated the aforementioned steps to prepare β-form of Aztreonam, the said procedure requires seeding at step(c) prior to the isolation without which said β- form of Aztreonam could not be obtained. Hence, according to this invention, it has become mandatory to include the procedure of seeding at step (c).

PL 178521 teaches the process for the preparation of aztreonam by treating tertiary butyl ester of aztreonam with monocarboxlyic acid like acetic acid, trichloroacetic acid, trifluroacetic acid or formic acid.

In view of the commercial importance of Aztreonam, there remains a need to find out simple and commercially viable process for the hydrolysis of t-butyl ester of Aztreonam of formula (II). Hence we focused our study, and succeeded with a process, which obviates the drawbacks in the prior arts, and yields Aztreonam in good quality and yield.

Objective of the Invention

The main objective of the present invention is to provide a simple industrially viable process for the preparation of Aztreonam.

Another objective of the present invention is to provide process for the preparation of Aztreonam, which obviates the problem of degradation to give high yields of Aztreonam in good purity.

Still another objective of the present invention is to provide a commercially viable process, which is less expensive than the prior art process and which could be implemented on the industrial scale.

Summary of the Invention

Accordingly, the present invention provides a process for the preparation of Aztreonam (I), which comprises the steps of

i) reacting [3S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)[l-t-butoxycarbonyl-l- methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-l-azetidinesulfonic acid (t-butyl ester of Aztreonam) of formula (II) with carboxylic acid of formula R-COOH, wherein R is selected from hydrogen or (substituted) alkyl and an acid in the presence or absence of a co-solvent; and ii) isolating Aztreonam of formula (I) in pure form.

The process is shown in Scheme- 1 :

Aztreonam ( alpha form)

Scheme-1

Detailed description of the invention

In an embodiment of the present invention, the acid employed in step (i) is selected from concentrated hydrochloric acid, methane sulfonic acid, p-toluene sulfonic acid, sulfuric acid and carboxylic acid of formula R-COOH is selected from group selected from formic acid, acetic acid, trichloroacetic acid, trifluroacetic acid and the like.

In another embodiment of the present invention, the hydrolysis reaction is carried out at temperatures, preferably between -5 ⁰C and 40 ⁰C. In another embodiment of the present invention the co-solvent employed in step (i) is selected from acetonitrile, propionitrile, dioxane, tetrahydrofuran, dichloromethane (MDC), ethyl acetate, toluene, IPE, acetone and the like.

In another embodiment of the present invention the hydrochloric acid employed can be added either commercially available con. HCl (37%) or can be passed as gas or HCl gas dissolved in any organic solvent.

In still another embodiment of the present invention the Aztreonam obtained was optionally purified by using acid base technique or solvent precipitation technique or by crystallization technique.

In one more embodiment of the present invention the oc-form of Aztreonam obtained was converted to β-form of Aztreonam by utilizing conventional techniques. The β-form of Aztreonam was blended with Arginine and lyophilized.

In yet another embodiment, the present invention provides a process for the preparation of sterile Aztreonam. The said process comprises steps of: a) dissolving the oc-form of Aztreonam in an organic solvent selected from the group comprising of absolute alcohols such as ethanol, methanol, isopropanol and the like in the presence of base at 0⁰C- 25⁰C; b) subjecting the clear solution obtained in step (a) to micron filtration; c) adjusting pH of the step (b) filtrate to 2.0-3.0 using an organic acid; d) optionally raising the temperature to 3O⁰C; and e) isolating sterile Aztreonam. In one more embodiment, this invention provides a process wherein the use of ethanolic HCl was avoided and organic acid such as methanesulfonic acid, formic acid was utilized for the pH adjustment. Since the use of ethanolic HCl in the sterile area creates problem of corrosion and handling problem etc., there remains a need to provide alternate method to avoid these practical implications and the present invention provides procedure to get rid of such implications. Accordingly the organic solvent used in step (a) is selected from the group consisting of ethanol, methanol, isopropanol or the mixtures thereof and the base used is ethanolic ammonia or an organic amine selected from triethyl amine or TMG.

In still another embodiment of the present invention, the starting material, Aztreonam t-butyl ester can be prepared by reacting Azetidine, (3S,4S)-3-amino-4- methyl-2-oxo-azetidine-l -sulfonic acid, with TAEM ((Z)-2-(-2-aminothiazoly-4- yl)-2-(t-butoxycarbonyl)-isopropoxyiminoacetic acid, benzothiazole-2-yl-thioester) as disclosed in various prior art or as described in reference Example.

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

Synthesis of Aztreonam

To t-butyl ester of Aztreonam of formula II (10 g), prepared according to the reference example was added formic acid (20 mL) in one lot and cooled to -5°C. Concentrated hydrochloric acid (5 mL) was added drop wise at -5⁰C to +2°C. The reaction mass was stirred at 15-20⁰C for 1.5 h. To the reaction mass was added cold ethyl acetate (150 mL) followed by cold water (150 mL) and stirred for 1.5 hours at 0-5°C. The solid obtained was filtered, washed with cold water (75 mL) and cold acetone (60 mL) and dried in air to yield the title compound (6.0 g).

Example 2: Preparation of Aztreonam (D

To t-butyl ester of Aztreonam of formula II, (25 g) was added mixture of acetic acid (75 mL) and concentrated hydrochloric acid (75 mL) at O⁰C to 5⁰C and stirred till completion of reaction. After completion of reaction, ethyl acetate (375 mL) and water (250 mL) were added at 0⁰C to 5°C. Stirred for 1 hour and solid obtained was filtered and washed with water. The solid obtained was dissolved using sodium bicarbonate solution and then clear aqueous solution was charcolised. The pH of the clear solution was adjusted to 2.0 by adding dil.HCl. The solid obtained was filtered, washed with water followed by acetone, and dried to yield the title compound. (Yield: 16.0 g).

Example 3;

Preparation of α- Aztreonam

To t-butyl ester of Aztreonam of formula II, (25 g) was added acetic acid (75 mL) and 37% hydrochloric acid (75 mL) at 0⁰C to 5°C and stirred for 2 to 3 hours. After completion of the reaction, the reaction mixture was quenched with cold water and stirred for one hour. The solid obtained was filtered and washed with water. The solid obtained was dissolved using sodium bicarbonate solution and subjected to carbon treatment. To the clear solution EDTA was added and pH of the clear solution was adjusted to 2.0 by adding dil.HCl. The solid obtained was filtered, washed with water followed by acetone, and dried to yield the title compound. (Yield: 16.0 g). Example 4:

Preparation of α-Aztreonam

To t-butyl ester of Aztreonam of formula II, (25 g) was added to acetic acid (75 niL) and concentrated hydrochloric acid (75 mL) at 0⁰C to 5⁰C and stirred for 2 to 3 hours. After completion of reaction, MDC (250 mL) and water (50 mL) were added at 0⁰C to 5°C. Organic layer was separated and stir the aqueous layer for 1 hour. The solid obtained was optionally purified as per example 2 to yield title compound. (Yield: 16.0 g)

Example 5:

Preparation of α- Aztreonam

To t-butyl ester of Aztreonam of formula II, (25 g) was added mixture of acetic acid (75 mL) and concentrated hydrochloric acid (75 mL) at 0⁰C to 5°C and stirred for 2 to 3 hours. After completion of reaction, the reaction mixture was quenched with MDC (250 mL) and water (50 mL). Organic layer was separated and pH of the aqueous layer was adjusted to 2.0 using 15% aqueous ammonia. After stirring for 1 hour, the solid obtained was filtered, washed and dried. (Yield: 16.0 B)-

Example 6;

Preparation of Aztreonam

To the mixture of acetic acid (75 mL) and concentrated hydrochloric acid (50 mL) and MDC (125 mL) t-butyl ester of Aztreonam of formula (II) (25 g) was added at O⁰C to 5⁰C and stirred for 2 to 3 hours. After completion of reaction, the solid obtained was filtered, washed with MDC to yield Aztreonam in pure form. Example 7;

Preparation of Aztreonam

To a mixture of acetic acid (75 mL) and concentrated hydrochloric acid (50 niL) and MDC (125 mL), t-butyl ester of Aztreonam of formula (II) (25 g) was added at 0⁰C to 5⁰C and stir for 2 to 3 hours. After completion of reaction, the solid obtained was filtered, washed with MDC. The Aztreonam obtained was dissolved in aqueous bicarbonate solution and pH of the aqueous layer was adjusted to 2.0 using

HCl. After stirring for 1 hour, the solid obtained was filtered, washed and dried

(Yield: 2Og).

Example 8:

Preparation of Aztreonam

To the mixture of acetic acid (75 mL) and concentrated hydrochloric acid (50 mL) and MDC (125 mL) t-butyl ester of Aztreonam of formula (II) (25 g), was added at O⁰C to 5⁰C and stir for 2 to 3 hours. After completion of reaction the pH was adjusted to 2.0 using TEA, the solid obtained was filtered, washed with MDC.

The Aztreonam obtained was dissolved in aqueous bicarbonate solution and pH of the aqueous layer was adjusted to 2.0 using HCl. After stirring for 1 hour, the solid obtained was filtered, washed and dried. (Yield: 20 g).

Example 9

Preparation of Sterile Aztreonam

To Aztreonam oc-form (25 g) in ethanol (250 mL) at 0⁰C to 5⁰C was added ethanolic ammonia solution. The clear solution obtained was filtered through 0.2 micron paper. The solution was cooled to 0⁰C and methane sulfonic acid (5 mL) was added to adjust the pH to 2.0-3.0. The solution was warmed to room temperature, stirred for one hour and cooled to 0⁰C under stirring. The solid obtained was filtered and washed with ethanol (50 niL). The wet material was stirred with ethanol for 5 h at room temperature, filtered and dried to get pure aztreonam (Yield: 17 g)

Example 10

Preparation of Sterile Aztreonam

To Aztreonam (25 g) in ethanol (250 mL) at 25°C was added ethanolic ammonia solution. The clear solution obtained was filtered through 0.2 micron paper. To the solution, methane sulfonic acid (5 mL) was added to adjust the pH to 2.0-3.0 at 25°C. The solution stirred for one hour. The solid obtained was filtered and washed with ethanol (50 mL). Solid obtained was stirred with ethanol for 5 h at room temperature, filtered and dried to yield β-form (Yield: 17 g)

Reference Example: Synthesis of t-butyl ester of Aztreonam of formula (II) To a suspension of Azetidine of formula III (25 g) in mixture of aq.acetone or aq.THF, triethylamine (29 mL) was added. To the reaction mass, TAEM of formula (IV) (75 g) was added and the reaction mass was stirred at 15⁰C -2O⁰C till completion of reaction. After completion of reaction was added a mixture of ethyl acetate and water (1 :1) and pH adjusted to 5.0. The by products obtained were removed, and layers separated. Organic layer was again extracted with water. The pH of the aqueous layer was acidified to 2.0 with dil. HCl at 0⁰C -5⁰C. The solid obtained was filtered, washed with water and dried under vacuum at 4O⁰C to yield title compound in pure form (48 g)

Claims

We claim:

1) A process for the preparation of Aztreonam comprising i. reacting [3S-[3α(Z),4β]]-3-[[(2-amino-4-miazolyl)[l-t-butoxycarbonyl- 1 -methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo- 1 -azetidinesulfonic acid (t-butyl ester of Aztreonam) of formula (II)

with carboxylic acid of formula R-COOH, wherein R is selected from hydrogen or (substituted) alkyl and an acid in the presence or absence of a co-solvent; wherein the improvement consists of usage of mixture of carboxylic acid of formula R-COOH and an acid and ii. isolating Aztreonam of formula (I) in pure form.

2) A process according to step (i) of claim 1, wherein the acid is selected from concentrated hydrochloric acid, methanesulphonic acid, PTSA or sulfuric aid.

3) A process according to Claim 1, wherein the mono carboxylic acid used in step (i) is selected from acetic acid, trifluroacetic acid, bromoacetic acid, chloroacetic acid or formic acid.

4) A process according to Claim 1, wherein the co-solvent used is selected from acetonitrile, propionitrile, dioxane, tetrahydrofuran, MDC, ethyl acetate, or toluene. 5) A process for the preparation of sterile form of Aztreonam, which comprises the steps of a) dissolving the Aztreonam in an organic solvent at 0°C to 25°C in the presence of a base and filtering through micron filtration; b) adjusting the pH of the step (a) filtrate to 2.0-3.0 using an organic acid; c) optionally raising the temperature to 3O⁰C; and d) isolating sterile Aztreonam

6) A process as claimed in claim 5, wherein the organic solvent used in step (a) is selected from ethanol, methanol, isopropanol or the mixtures thereof and the base used is ethanolic ammonia or an organic amine selected from triethyl amine or TMG.

7) A process as claimed in claim 5, wherein the organic acid used in step (b) is selected from methanesulfonic acid, formic acid, acetic acid or trifluroacetic acid.

8) A process as claimed in claim 5, wherein the Aztreonam obtained in step (d) is in β form.