HEMIHEPTAHYDRATE

The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the invention

The present invention is in the field of chemistry and more particularly it relates to the preparation of ceftriaxone disodium hemiheptahydratc of formula (I), reacting 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-l ,2,4-triazin-3-yl)thio|mcthyl}- 3-cephem-4-carboxylic acid of formula (II) with 2-mercaptobcn/.othia/.olc 2-(2- aminothiazol-4-yl)-2-syn-methoxyiminoacetate of formula (III) in presence of a base and using alcohol as a solvent in a very safe, simple, economical, uscr-fricndly and in an industrially viable manner.

(II) (III)

Background of the invention .

Ceftriaxone disodium hemiheptahydrate of formula (I), is chemically known as disodium salt 7-{r2-(2-aminothiazol-4-yl)-2-syn-methoxyimino| acctamido}-3-{|(2,5- dih ydro-6-hydroxy-2-methyl-5-oxo-l ,2,4-triazin-3-yl)thio|mcthyl}-3-ccphcm-4- carboxylic acid. Ceftriaxone is a cephalosporin of a great therapeutical interest due to its effective antibacterial activity; and is administered as disodium salt hemiheptahydrate. It finds application in the treatment of several infections.

(D

All relevant processes described in literature starts with 7-amino-3-{|(2.5- dihydro-ό-hydroxy^-methyl-S-oxo-l ^^-triazin^-y^thioJmethyll^-ccphcm^- carboxylic acid of formula (II) whereby the side chain in N-protectcd or unprotected form is introduced into the amino group in position 7 using various acylation techniques.

The most elegant method of introducing the side chain uses a reactive thiocstcr. e.g. 2-mercaptobenzothiazole 2-(2-aminothiazol-4-yl)-2-syn-mcthoxyiminoacctatc of formula (III), as here it is not necessary to protect the amino function of the 2- aminothiazolyl group. This process was first described in EP-Λ-0037380 (Biochcmic GmbH) henceforth '380, and since then has been used in a few slightly modified processes such as EP-A-0399094 (Synthetic Biolog Dev.), henceforth "094.

Patent '380 describes a preparation which starts from 7-amino-3-(2,5-dihydro- ό-hydroxy^-methyl-S-oxo-l ^^-triazin-S-yOthiomethyl^-cephem^-carboxylic acid of formula (II), which suitably protected at the carboxylic group, is made to react with 2-mercaptobenzothiazole 2-(2-aminothiazol-4-yl)-2-synmcthoxyimino acetate, then, after being deprotected, it gives ceftriaxone in the form of free acid. Its corresponding transformation in its soluble form as disodium salt is carried out afterwards according to the known techniques.

Another process, which operates without a protecting group at the amino function of the aminothiazole, is described in EP-A-0175814 (Hanmi Pharma Ind Co Ltd). In this process, active esters with 1-hydroxybenzotriazole arc employed. Processes using an amino protecting group arc described in Gli-Λ-2022090 (Hoffmann La Roche) and in '094. Of all the processes described, the one using activated thioester, as described in the patent '380, appears to be the best.

According to the patent '380, 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-mcthyl-5- oxo-l,2,4-triazin-3-yl)thio]methyl}-3-cephem-4-carboxylic acid of formula (II) is silylated in dichloromethane with N,O-bis-(trimethylsilyl)acctamidc and reacted with 2-mercaptobenzothiazole 2-(2-aminothiazol-4-yl)-2-syn-mcthoxyirninoacctatc of formula (III),. By adding methanol-containing acetonitrile, the ceftriaxone formed is precipitated as a free acid. This then has to be converted in a further reaction step into the desired form of the disodium salt.

In the process described in patent '380, not only an ecologically hazardous chlorinated hydrocarbon (dichloromethane) is used as the reaction solvent which is difficult to recycle or dispose of in an environmentally acceptable manner, but also the toxic acetonitrile is employed to isolate the active substance. In this process, mother liquor is obtained, which consists of a mixture of dichloromethane, methanol, acetonitrile, acetamide and siloxanes. Apart from the ecologically hazardous dichloromethane, this mixture also contains the solvents methanol and acetonitrile. and in addition the suspected carcinogenic acetamide. Regeneration of the individual components from this mixture may only be carried out at very great expense, if at all. A further disadvantage of the process described in the patent '380 is that first of all ceftriaxone has to be isolated, and in an additional step of the process, the disodium sail form thereof which is necessary for parenteral application must be produced.

In the process described in patent '094, the reaction of 7-amino-3-{|(2.5- dihydro-6-hydroxy-2-methyl-5-oxo-l ,2,4-triazin-3-yl)thio]methyl}-3-cephcm-4- carboxylic acid of formula (II) with 2-mercaptobenzothiazole 2-(2-aminothiazol-4vyl)- 2-syn-methoxyiminoacetate of formula (III) is effected in a mixture of dimethylacetamide, tetrahydrofuran and water. In order to be able to isolate . a product of high purity, in this process first of all the N,N-dibenzylethylcnediaminc salt of ceftriaxone must be produced. For this, two further solvents arc employed, namely ethyl acetate and dichloromethane, so that the mother liquor to be regenerated is finally a mixture of 5 different solvents, containing again the ecologically hazardous dichloromethane. Finally, in order to produce the desired ceftriaxone disodium salt hemiheptahydrate, acetone is required. In this process, the result is thus a mixture of solvents, the regeneration of which into pure individual components in an economical manner is not possible. In addition, two isolation steps are necessary to obtain the desired product.

Accordingly therefore, there is an urgent need to develop an alternative industrially viable process for the preparation of a compound of formula (I), which is readily amenable to scale-up. Hence we focused our research to simplify the process for the preparation of a compound of formula (I) by using alcoholic solvent and substantially low amounts of reagent(s) and solvent(s), in a substantially lesser reaction time, while getting a greater yield with higher purity and avoiding unwanted by products and impurities by using substantially different method of making thereof to obviate the aforesaid problems associated with the prior art proccss(s).

As discussed above none of the prior art references disclosed or claimed the use of alcoholic solvent for the preparation of compound of formula (I), for the condensation of 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo- l ,2.4-lria/in-3- yl)thio]methyl}-3-cephem-4-carboxylic acid of formula (II) with 2- mercaptobenzothiazole 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacctatc of formula (III), hence we focused our research to develop an improved and efficient process for the preparation of a compound of formula (I) along with substantially fair operational safety, satisfactory yield and high chemical purity, which makes the process more economical, distinct and successful at industrial & commercial level.

It should be pointed out that the said condensation, which is extremely aggressive, in alcoholic solvents and mixtures thereof, has never before been reported in literature. The present invention provides remarkable advantages in the industrial processes for the production of ceftriaxone disodium hemiheptahydrate. In fact, the method of the invention provides good quality ceftriaxone disodium hemiheptahydrate of formula (I) in yields quite comparable to those expected with the prior art methods. Objective of the invention

The main object of the present invention is to provide a process for the preparation of a compound of formula (I), which is very safe, simple, economical, iiscr- friendly and commercially viable.

Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvcnt(s) and to avoid hazardous and risky solvents, which makes the present invention more safe and eco-friendly as well.

Yet another objective of the present invention is to provide a process for the preparation of a compound of formula (I) in a greater yield with higher chemical purity.

Still another objective of the present invention is to provide a process for the preparation of a compound of formula (I), wherein the alcoholic solvent used during the reaction can be reusable and thereby recyclable, which makes the process industrially more suitable.

Summary of the invention

Accordingly, the present invention provides a process for the preparation of ceftriaxone disodium hemiheptahydrate of formula (I), which comprises the steps of:

(I)

(i) condensing 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo- l ,2.4-tria/in- 3-yl)thio]methyl}-3-cephem-4-carboxylic acid of formula (II) with 2-mercaptobenzothiazole 2-(2-aminothiazol-4-yl)-2-syn-mcthoxyiminoacctatc of formula (III) in presence of a base in an alcoholic solvent; (ii) adding water and an organic solvent;

(iii) separating the organic layer and aqueous layer;

(iv) adjusting the pH of aqueous layer as obtained from step (iii) with an acid;

(v) adding sodium ion source and an organic solvent to the aqueous layer as obtained from step (iv); and

(vi) isolating the ceftriaxone disodium hemihcptahydratc of formula (I) in pure form.

The above process is illustrated in the following synthetic scheme:

(II) (IW

Base

Alcoholic solvent

(I)

Detailed description of the invention

Accordingly in an embodiment of the present invention, the said alcoholic solvent in step (i) may be selected from the group consisting of methanol, ethanol. isopropanol, tertiary butyl alcohol and the like or mixture thereof, more preferably methanol.

In another embodiment of the present invention, the said base in step (i) is an organic base which may be selected from the group consisting of tricthylaminc. pyridine, N-methylpiperidine, 1,8-diazabicycloundecene, 4,4-dimcthylaminopyridinc, dicyclo hexylamine, diphenylaminc, diisopropylaminc, N-tcrt-butylcyclohcxylaminc and N,N-dibenzylethylenediamine and the like or mixtures thereof, more preferably triethylamine.

In another embodiment of the present invention, the condensation of step (i) is performed at a low temperature, preferably in the range of -10 ⁰ C to 10 ⁰ C.

In another embodiment of the present invention, the condensation of step (i) is accomplished relatively in a shorter time, which makes the process more useful against the prior art processes. The said condensation of step (i) is proceeding to completion in 1 to 4 hrs.

In another embodiment of the present invention, the said organic solvent in step (ii) is n -butyl acetate or ethyl acetate.

In another embodiment of the present invention, the said acid in step (iv) is hydrochloric acid or sulfuric acid and the like, more preferably hydrochloric acid.

In another embodiment of the present invention, the pH disclosed in step (iv) is in the range of 5 to 7, more preferably 6.0 to 6.3.

In another embodiment of the present invention, the said sodium ion source in step (v) may be selected from the group consisting of sodium hydroxide, sodium acetate or sodium 2-ethylhexanoate and the like, - more preferably sodium 2- ethylhexanoate.

In another embodiment of the present invention, the said organic solvent in step (v) is a ketonic solvent which may be selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, methyl tertiary butyl ketone and mixture thereof or alcoholic solvent which may be selected from the group consisting of methanol, ethanol, isopropyl alcohol, tertiary butyl alcohol and mixture thereof. In another embodiment of the present invention, all the steps except step (i) arc preferably performed at a temperature in the range of -10 ⁰ C to reflux temperature of the solvent used.

In the present invention starting material(s) for the preparation of a compound of formula (I), were prepared according to the known processes in the prior art.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXAMPLE 1

Preparation of disodium salt of ceftriaxone hemiheptahydrate

1.0 kg of 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-l ,2,4-tria/in-3- yl)thio]methyl}-3-cephem-4-carboxy!ic acid and 1.04 kg of 2-mercaptobenzothia/olc 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetate were added in 4.5 L of methanol at O ⁰ C to 5 ⁰ C and 0.5 L of methanol was flushed into the reactor. The mixture was kept at (-) 2 ⁰ C to 2 ⁰ C and 0.55 kg of triethylamine was dropwise added under stirring over 30 mins. The solution was stirred at O ⁰ C to 3 ⁰ C until the reaction was completed. Subsequently, 0.02 kg sodium metabisulphite, 6 L water and 10 L /?-butyl acetate were added at 3 ⁰ C to 7 ⁰ C. The reaction mixture was stirred for 15 to20 mins and settled at 2O ⁰ C to 25 ⁰ C. The aqueous phase was separated and pH was adjusted to 6.0 to 6.3 with dilute hydrochloric acid solution. 0.02 kg ethylenediaminetetraacctic acid and 0.01 kg sodium metabisulphite were added thereto under stirring at 25 ⁰ C to 3O ⁰ C. Λ solution consisting of 1.1 kg sodium 2-ethylhexanoate in 5 L acetone was added to the reaction mixture within 1 hr at 26 ⁰ C to 3O ⁰ C under stirring. Afterwards 25.0 L of acetone was added dropwise and the resulting crystal suspension was stirred further for 1 hr at the same temperature .The material was filtered, washed with 2 L of acetone and dried in a vacuum drying chamber at 4O ⁰ C for 3 hrs to get 1.65 kg (92.7 %) of the title compound with 99.79 % chromatographic purity. EXAMPLE 2

Preparation of disodium salt of ceftriaxone hemihcptahydratc

1.0 kg of 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-mcthyl-5-oxo- 1.2,4-tria/in-3- yl)thio]methyl}-3-cephem-4-carboxylic acid and 1.04 kg of 2-mercaptobcnzolhia/.olc 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetate were added in 4.5 I. of ethanol at O ⁰ C to 5 ⁰ C and 0.5 L of ethanol was flushed into the reactor. The mixture was kept at (-) 2 ⁰ C to 2 ⁰ C and 0.55 kg of triethylamine was dropwise added under stirring over 30 mins. The solution was stirred at O ⁰ C to 3 ⁰ C until the reaction was completed. Subsequently, 0.02 kg sodium metabisulphite, 6 L water and 10 L /7-butyl acetate were added at 3 ⁰ C to 7 ⁰ C. The reaction mixture was stirred for 15 to20 mins and settled at 2O ⁰ C to 25°C. The aqueous phase was separated and pH was adjusted to 6.0 to 6.3 with dilute hydrochloric acid solution. 0.02 kg ethylenediaminctetraacctic acid and 0.01 kg sodium metabisulphite were added thereto under stirring at 25 ⁰ C to 3O ⁰ C. Λ solution consisting of 1.1 kg sodium 2-ethylhexanoate in 5 L ethanol was added to the reaction mixture within 1 hr at 26 ⁰ C to 3O ⁰ C under stirring. Afterwards 30.0 L of ethanol was added dropwise and the resulting crystal suspension was stirred further for 1 hr at the same temperature .The material was filtered, washed with 2 L of ethanol and dried in a vacuum drying chamber at 4O ⁰ C for 3 hrs to get 1.65 kg (92.7 %) of the title compound with 99.75 % chromatographic purity.

EXAMPLE 3

Preparation of disodium salt of ceftriaxone hemihcptahydratc

1.0 kg of 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1.2,4-tria /in-3- yl)thio]methyl}-3-cephem-4-carboxylic acid and 1 .04 kg of 2-mcrcaptoben/othia/olc 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetatc were added in 4.5 L oC methanol at O ⁰ C to 5°C and 0.5 L of methanol was flushed into the reactor. The mixture was kept at (-) 2 ⁰ C to 2 ⁰ C and 0.55 kg of triethylamine was dropwise added under stirring over 30 mins. The solution was stirred at O ⁰ C to 3 ⁰ C until the reaction was completed. Subsequently, 0.02 kg sodium metabisulphite, 6 L water and 10 L rø-butyl acetate were added at 3 ⁰ C to 7 ⁰ C. The reaction mixture was stirred for 15 to20 mins and settled at 2O ⁰ C to 25 ⁰ C. The aqueous phase was separated and pH was adjusted to 6.0 to 6.3 with dilute hydrochloric acid solution. 0.02 kg ethylenediaminetctraacetic acid and 0.01 kg sodium metabisulphite were added thereto under stirring at 25 ⁰ C to 3O ⁰ C. Λ solution consisting of 1.1 kg sodium 2-ethylhexanoate in 5 L isopropanol was added to the ^• reaction mixture within 1 hr at 26 ⁰ C to 3O ⁰ C under stirring. Afterwards 35.0 L of isopropanol was added dropwise and the resulting crystal suspension was stirred further for 1 hr at the same temperature .The material was filtered, washed with 2 \ , of isopropanol and dried in a vacuum drying chamber at 4O ⁰ C for 3 hrs to get 1 .66 kg to 1.70 kg (93.2 % to 95.5 %) of the title compound with 99.60 % chromatographic purity.

EXAMPLE 4

Preparation of disodium salt of ceftriaxone hemihcptahydratc

1.0 kg of 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-mcthyl-5-oxo- 1.2,4-triazin-3- yl)thio]methyl}-3-cephem-4-carboxylic acid and 1.04 kg of 2-mcrcaptobcnzothia/o!c 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetate were added in 4.5 L of methanol at O ⁰ C to 5 ⁰ C and 0.5 L of methanol was flushed into the reactor. The mixture was kept at (-) 2 ⁰ C to 2 ⁰ C and 0.55 kg of triethylamine was dropwise added under stirring over 30 mins. The solution was stirred at O ⁰ C to 3 ⁰ C until the reaction was completed. Subsequently, 0.02 kg sodium metabisulphite, 6 L water and 10 L n-butyl acetate were added at 3 ⁰ C to 7 ⁰ C. The reaction mixture was stirred for 15 to20 mins and settled at 2O ⁰ C to 25 ⁰ C. The aqueous phase was separated and pH was adjusted to 6.0 to 6.3 with dilute hydrochloric acid solution. 0.02 kg ethylenediaminetctraacetic acid and 0.01 kg sodium metabisulphite were added thereto under stirring at 25 ⁰ C to 3O ⁰ C. Λ solution consisting of 1.1 kg sodium 2-ethylhexanoate in 5 L ethanol was added to the reaction mixture within 1 hr at 26 ⁰ C to 3O ⁰ C under stirring. Afterwards 25.0 L of ethanol was added dropwise and the resulting crystal suspension was stirred further for 1 hr at the same temperature .The material was filtered, washed with 2 L of ethanol and dried in a vacuum drying chamber at 4O ⁰ C for 3 hrs to get 1.65 kg (92.7 %) of the title compound with 99.89 % chromatographic purity. Substantial Advantages and Industrial applicability

(1) The process of the present invention is very safe, simple and yields higher purity and greater yield of a compound of formula (1).

(2) The process of the present invention avoids excess usages of rcagent(s) and organic solvent(s), thereby promoting green chemistry and ensuring a cleaner surrounding by putting less load on environment.

(3) The process of the present invention avoids the use of solvents like tctrahydrofuran. dichloromethane, N,N-dimethylformamide, acetonitrile which arc harmful for the environment and are very hazardous in nature.

(4) The process of the present invention uses a solvent which can be recycled and reused. This makes the process more economical and industrially & commercially viable.

(5) The process of the present invention is a simple process, which avoids more number of operations, thus resulting in shortening of reaction time and lowering of labor.