WO2023181045A1

WO2023181045A1 - Process for the preparation of carcinogenic azido impurities free losartan and salts thereof

Info

Publication number: WO2023181045A1
Application number: PCT/IN2022/050435
Authority: WO
Inventors: Sumit S. CHOURASIYA; Kamlesh J. RANBHAN; Vipin Kumar; Anandita .
Original assignee: Iol Chemicals And Pharmaceuticals Limited
Priority date: 2022-03-22
Filing date: 2022-05-06
Publication date: 2023-09-28

Abstract

Process for the preparation of carcinogenic azido impurities free Losartan and salts thereof Comprising using sartan catalyst that alleviates or minimizes carcinogenic impurities preferably Losartan azido of Formula III up to pharmaceutically acceptable limit.

Description

PROCESS FOR THE PREPARATION OF CARCINOGENIC AZIDO IMPURITIES

FREE LOSARTAN AND SALTS THEREOF

FIELD OF INVENTION:

Disclosed herein is a process for the preparation of sartan preferably Losartan and its potassium salt represented by of formula I and formula II respectively, characterized by the feature that all the well-known mutagenic/carcinogenic impurities depicted herein in Figure 1 and falling under the Azido family are either absent or present within the pharmaceutically acceptable limits (Also referred herein as level). In particular, the process of the present invention provides an improved process for the preparation of Losartan potassium depicted in SCHEME-2 to alleviate the formation thus presence of carcinogenic azido impurities particularly impurity namely (5-(4'-((5- (azidomethyl)-2-butyl-4-chloro- 1 H imidazol- 1 -yl)methyl)- [ 1 , 1 '-biphenyl] -2-yl)- 1 H tetrazole) also referred herein as Losartan azido of formula III an)

FORMULA II (Losartan potassium)

Formula III (Losartan Azido/ Azido Losartan)

Losartan Cyano alcohol

Formula IV (Losartan cyanoalcohol)

Formula V (Losartan sodium)

BACKGROUND OF THE INVENTION:

Sartans are all prescription angiotensin receptor blocker (ARB) drugs, which are a class of drugs used to treat patients with high blood pressure to prevent heart attacks and stroke. They are also used in patients with heart failure or those who have had a recent heart attack. In particular, Losartan potassium of formula II a non-peptide molecule is chemically described as 2-butyl-4- chloro-l-[p-(o-lHtetrazol-5-ylphenyl)benzyl]imidazole-5 -methanol potassium salt.

The azido impurity e.g. 5-(4'-(azidomethyl)-[l,T-biphenyl]-2yl)-lH-tetrazole and related ones, are considered as mutagens. “A mutagen is a chemical substance that can cause a change in the DNA of a cell”. These mutations may increase the risk of cancer. There are established international guidelines that recommends that mutagenic impurities to be kept at or below a specific level because exposure to a mutagen over the long term at a level above (what is considered to be safe), has the potential to increase the risk of cancer.

In 2018, several “sartan” medicines were recalled due to nitrosamine impurities. The present investigation relates to azide impurity being cropped up as another current hot issue and is unrelated to that of nitrosamine impurity, although both impurities have similar safety concerns.

The impurity, known as azidomethyl-biphenyl-tetrazole (AZBT), is a compound that gets formed during the manufacture of the active ingredient in some sartan medicines. It is known to damage DNA, and as a result long-term exposure over years may increase an individual's risk of developing cancer. Recent investigations currently resulted in the identification of Losartan azido impurity of Formula III referred as Azido Losartan namely 5-[4'-[(5-(azidomethyl)-2-butyl-4- chloro-lH-imidazol-l-yl)methyl]-[l,l'-biphenyl]2-yl]-lH-tetrazole that has so far only been detected in Losartan potassium. The said impurity is also referred as “Losartan azido impurity” has tested positive in a bacterial mutagenicity (Ames) test. In the absence of additional information from in vivo studies, it is necessary to ensure that this azido impurity is controlled at or below the pharmaceutically acceptable limits.

Recently, multiple batches of Losartan potassium have been recalled from the market by FDA due to the presence of carcinogenic impurities belonging to the Azido family, of which Azidomethylbiphenyl tetrazole (AZBT), Azidomethylbiphenyl carbonitrile (AZBC) and Losartan azido are some of the identified azido impurities that have proven to be carcinogenic by Ames test. In very recent time many of the pharma companies like Mint Pharmaceuticals Inc, Auro Pharma Inc, Pharmascience Inc. and Sivem Pharmaceuticals, Sandoz Canada Inc, Sanis Health Inc, had recalled lots of its prescription Losartan tablets, in 25 mg, 50 mg and 100 mg strengths, after tests found an azido impurity of Losartan (Losartan azido) namely (5-(4'-((5-(azidomethyl)- 2-butyl-4-chloro-lH imidazol-l-yl)methyl)-[l,l'-biphenyl]-2-yl)-lH tetrazole) above the acceptable limit.

The Azido impurities are characterized by the azide functional group (-N=N=N) in an organic molecule. These impurities are mainly formed in a process during tetrazole ring formation wherein metal azide and triethylamine hydrochloride is used. There are many processes to prepare Losartan and its pharmaceutical salts that are disclosed in the literature. Various carcinogenic azido impurities such as azidomethylbiphenyl tetr azole (AZBT), azidomethylbiphenyl carbonitrile (AZBC), Losartan azido, BCFI azido, Azidomethylbiphenyl carboxylic acid (AZBA), Azidomethylbiphenyl carboxamide (AZBX) etc. are represented in Figure I as given herein below.

Losartan Azido BCFI Azido

FIGURE-I: LIST OF POSSIBLE AZIDO IMPURITY In 1982, Furukawa, Kishimoto and Nishikawa of Taketa Chemical Indus, discovered a class of non-peptide-containing imidazoles that also inhibited the vaso constriction effect of angiotensin II.

US5138069 discloses another class of imidazoles, which encompasses the compound Losartan in 1995, Losartan (CA Index: 2-butyl-4-chloro-l-[[2'-(lH-tetrazol-5-yl) [ 1,1 '-biphenyl] -4- yl]methyl] - 1 H-imidazole-5 -methanol).

EP253310 discloses a process, wherein 2-n-butyl-4-chloro-l H-imidazolyl-5- melhanol (III) is coupled with 5-(4'-bromomethyl-l , 1 '-biphenyl-2-yl)-2- triphenylmethyl-2H-tetrazole (IV) in N, N-dimethylformamide as solvent in presence of sodium methoxide as the base to furnish trityl Losartan (V).

The drawback associated with this prior art is that this coupling reaction results in a mixture of trityl Losartan and its regioisomer (V). These are separated by column chromatography.

US5155118 (hereinafter referred as ‘118) disclose a process for making Trityl Losartan, wherein coupling between the compound of formula (V) and the compound of formula (II) is carried out in a biphasic solvent system comprising chlorinated solvent and water. The reaction is carried out at room temperature in presence of sodium hydroxide as the base and aliquot 336 as the phase transfer catalyst. The resulting intermediate (VI) is then reduced in situ with sodium borohydride to furnish trityl Losartan of formula (III) in low yield.

Although ‘118 discloses the use of “aliquot 336” as a catalyst but the intension was not same as of present invention i.e. to minimize the azido impurity. It was used as a phase transfer catalyst as the reaction was biphasic.

Two main routes (Route 1 and Route 2) are followed for the preparation of Losartan potassium, among them route 2 is most commonly used in industry. Route 1 comprises incorporation of tetrazole moiety to 2-Cyano -4-Methyl Biphenyl (OTBN) followed by bromination, BCFI coupling, reduction and finally Losartan potassium salt formation.

Route-1

Losartan Potassium Losartan

Route 2 comprises bromination, BCFI coupling, reduction and finally Losartan potassium salt formation. Both the processes have their pros and cons. In route 1, the formation of azido impurity is less possible as OTBN is first reacted with metal azide to form tetrazole. As there is no other reactive site, formation of azido impurity is minimized. The main drawback of this route is lengthy process, use of toxic and expensive tributyltinchloride and protection/deprotection chemistry. In this context, route 2 have added advantage of short route, use of sodium azide as non-expensive reagent, however suffer from major drawback of formation of azido impurity.

Route-2

Losartan Potassium Losartan Losartan cyanoalcohol

The possible pathway for the formation of Losartan azido impurity in route 2 is demonstrated in scheme 1. Thus, it can be concluded that the formation of azido impurity cannot be ruled out when Losartan cyanoalcohol of Formula IV is treated with sodium azide and triethylamine hydrochloride. Unfortunately, these impurities are structurally similar to Losartan and thus very difficult to remove by purification method.

Scheme 1 : Possible pathways for the formation of Losartan azido impurity

A few prior art references disclose a process for the preparation of Losartan and salts thereof wherein non-azido impurities such as N-nitrosamines have been reported.

CN112679476 relates to a process for the quenching of residual unreacted metal azide present in the reaction mass using catalyst. The catalyst used for the quenching of residual azide ion is zinc chloride, tributyltin chloride, triethylamine hydrochloride, triethylamine sulfate, a mixture of triethylamine and hydrochloric acid, or a mixture of triethylamine and sulfuric acid. The sodium nitrite is not required for the quenching of azide ion and thus the formation of nitrosamine impurity is avoided.

There is no mention of azido impurity.

IN201941033425 is directed to a method for the preparation and purification of Losartan and its intermediates and pharmaceutically acceptable salts and solvates thereof; also, herein described are the compositions comprising substantially pure Losartan or salts thereof free of the N- nitrosamines impurities. There is no mention of azido impurity.

IN201841048710 relates to a process for the preparation of Sartan or salt thereof containing N- nitrosoalkylamine impurities below the limit of detection. Specific aspects relate to process for the preparation of Sartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities. There is no mention of azido impurity.

CN 110467604 (hereinafter referred as “7604) discloses a process for the preparation of Losartan comprising reaction of a cyano group-containing intermediate represented by formula (IV) with an azide reagent in toluene in the presence of a catalyst; after the completion of reaction, wherein, unreacted azide reagent are removed by adding water into reaction system thereby resulting into three layers, separating the middle layer and adding n-butanol to said layer for dilution, and adding triphenylphosphine to the resulting diluted solution so as to remove remaining unreacted azide reagent from the diluted solution. The absence of azide reagent from the reaction mass does not require the addition of sodium nitrite for azide quenching and thus limit the formation of nitrosamine impurity. However; the drawback associated with this process is the multiple layers formation and separation thereof, thereby making the process laborious and lengthier thus industrially unviable. Like above mentioned patents, patent 7604 also disclose the control of nitrosamine impurity only by controlling/removing unreacted azide reagent

(MN3). There is no mention of azido impurity.

None of the patents mentioned herein above talk about method for preparation of sartan that indicate or teach to a person skilled in the art to alleviate or minimize azido impurities with in pharmaceutically acceptable limits.

In view of above there is a dire need to develop a process for the preparation of Losartan and its salts preferably potassium salt as a product with controlled, low or even absence of azido impurities. Inventors of the present invention without any teaching or motivation from processes disclosed therein in the prior art analyzed using their intellect and expertise understood the chemistry responsible for formation and of undesired carcinogenic impurity of azido family and accordingly after an exhaustive R&D activity have developed and disclose herein an improved process for the preparation of sartan molecule particularly Losartan which is simple without any additional process of purification step and accordingly said novel and inventive improved process is economical, industrially scalable. Losartan or salts thereof obtained based on the said improved process is free of Azido impurity particularly Losartan azido impurity of Formula III or if present it is below LOD (level of detection) or within pharmaceutically acceptable Limit of NMT 10 ppm. Process of the present invention is illustrated in Scheme-2 herein below:

Scheme-2

OBJECTIVES OF THE INVENTION:

The main objective of the present invention is to provide an improved process for the preparation of sartan molecule that alleviates or minimizes the formation/presence of carcinogenic azido class of impurities which are generally formed during the preparation based on prior art process.

The major objective of the present invention is to provide an improved process for the preparation of Losartan potassium to alleviate or minimize the formation/presence of carcinogenic azido impurities and said process comprising the use of sulfur containing compound/metal catalyst referred herein as “Sartan catalyst ” that decomposes carcinogenic azido impurities into non-carcinogenic amine derivatives. pH of reaction mass containing said non-carcinogenic amine derivatives is adjusted to 3-4 by adding a mineral acid particularly HC1 as a result the said amine derivatives form water soluble salts and gets washed away and thus removed from the reaction mass containing sodium losartan of Formula V which also gets hydrolysed to produce Losartan of Formula I. During standard processing and isolation of Losartan of Formula I any non-carcinogenic amine water soluble amine derivative salt gets removed or minimized to pharmaceutically acceptable limit.

Inventors of the present invention would like to emphasize herein that the standard conventional process of preparing losartan of Formula I which doesn’t comprise using losartan catalyst and product formed is having up to 150 ppm losartan azido impurity of Formula III also comprises the use of HC1 to hydrolyse sodium losartan of Formula V to free losartan of Formula I, therefore, the only additional process is addition of losartan catalyst in situ without any additional process step followed by the standard process of adding acid which serves dual purposes viz formation of water soluble amine salt of the amine derivatives formed as a result of decomposition of azido impurities including losartan azide of Formula III and hydrolysis of losartan sodium of Formula V into water insoluble losartan of Formula I. The said amine derivatives being water soluble gets removed and washed away during the standard processing during the isolation of substantially pure losartan of Formula I free or of azido impurities including losartan azide of Formula III and if present then within pharmaceutally acceptable limit of lOppm.

As evident from Table- 1 and 2 herein the maximum losartan azide impurity present is less than 0.3ppm which is far less than lOppm which is pharmaceutically acceptable limit.

Another objective of the present invention is to provide an improved process for the preparation of Losartan and its potassium salt free from Losartan azido impurity of formula III or present within pharmaceutically acceptable limit which is not more than 10 ppm.

Another objective of the present invention is to provide an improved process for the preparation of Losartan of the formula I and its potassium salt with high purity without any additional purification steps.

Another objective of the present invention is to provide an improved process for the preparation of Losartan and its potassium salt to alleviate or minimize the formation/presence of carcinogenic azido impurities such as azidomethylbiphenyl tetr azole (AZBT), azidomethylbiphenyl carbonitrile (AZBC), Losartan azido, BCFI azido, Azidomethylbiphenyl carboxylic acid (AZBA), Azidomethylbiphenyl carboxamide (AZBX) etc represented in figure I herein before.

Another objective of the present invention is to use “sartan catalyst” for the preparation of azido impurities free sartans wherein azido impurities are formed due to the use of O-tolyl benzonitrile) (OTBN ) or 4'-(Bromomethyl)[l,l'-biphenyl]-2-carbonitrile (Bromo OTBN) as KSM during synthesis of Losartan.

Still another objective of the present invention is to use “sartan catalyst” to decompose carcinogenic azido impurities into corresponding non-carcinogenic amino derivatives which gets removed as described herein before during standard processing whilst isolating purified losartan of Formula I.

TECHNICAL PROBLEMS ASSOCIATED WITH THE PRIOR ART:

The most prominent shortcoming associated with process for the preparation of sartan drug molecule particularly Losartan is the formation of Azido impurities having functional group (- N=N=N). These impurities are mainly formed in a process during tetrazole ring formation wherein metal azide/trialkylammonium chloride is used as raw metrical. Various Azido impurities such as azidomethylbiphenyltetrazole (AZBT), azidomethylbiphenyl carbonitrile (AZBC), Losartan azido, BCFI azido, Azidomethylbiphenyl carboxylic acid (AZBA), Azidomethylbiphenyl carboxamide (AZBX) are carcinogenic/ mutagenic. Hence there is a need to develop an efficient process for the preparation of sartin particularly losartan and salt thereof wherein the carcinogenic azido impurity/ies are absent particularly losartan azido of Formula III and if present it is within the pharmaceutically acceptable limits.

TECHNICAL SOLUTION:

Considering various problems associated with work-up and isolation of the desired product according to process(es) disclosed therein in the prior art, there is a dire need to provide the solution to all the technical problems related to isolation of the product of interest with no or minimized level of azido impurities particularly Losartan azido of formula III.

Inventors of the present invention based on their expertise and R&D activity found that the presence of one or more carcinogenic azido impurities can be alleviated just by using a sulphur containing catalyst and/or metal catalyst referred herein as “sartan catalyst” ” that is capable of decomposing carcinogenic azido impurities including losartan azide of Formula III into corresponding non carcinogenic amine derivatives which as describe herein before form water soluble salt with an acid and gets removed during standard process of isolation of substantially pure losartan of Formula I and its potassium salt of Formula II which is either free from azido impurities particularly Losartan azido of formula III or if present are within pharmaceutically acceptable limit.

Sartan catalyst is selected from the group comprising sulfur containing agents or metal catalyst. Sulfur containing agent is selected from the group comprising sodium dithionite, sodium metabisulfite, sodium bisulfite, sodium sulfide or mixture thereof. Metal catalyst is selected from the group comprising Raney Ni/th, Pd/C/Fh, Raney Ni/th and the like or mixture thereof which can perform the same function.

As evident from foregoing the Inventors of the present invention disclose herein a novel and inventive process illustrated herein in Scheme-2 for the preparation of sartan drug molecule preferably Losartan and its potassium salt of Formulae I and II respectively having no or within pharmaceutically acceptable level the azido impurities particularly Losartan azido of formula III.

ADVANTAGES OF PRESENT INVENTION:

Major advantage of the present invention comprising the use of “SARTN CATALYST” that provides desired sartan preferably Losartan and its potassium salt free from all azido impurities preferably Losartan azido of Formula III and if present then to the extent of less than 0.3 ppm which is far less than pharmaceutically acceptable limit 10 ppm.

DEFINITION AND GENERAL TERMS: i. SARTANS: Sartans are Angiotensin-II-receptor antagonists containing a tetrazole group. Valsartan, Losartan, Irbesartan and other “-sartan” drugs are a class of medicines known as angiotensin II receptor blocker (ARBs) used to treat high blood pressure and heart failure. ii. TETRAZOLE: Tetrazoles are a class of synthetic organic heterocyclic compound, consisting of a 5-member ring comprising four nitrogen atoms and one carbon atom. The name tetrazole also refers to the parent compound with formula CH2N4 iii. AZIDO IMPURITIES: The Azido impurities are organic impurities that characterized by the azide functional group (-N=N=N) and are found to be carcinogenic / mutagenic in nature. iv. AZIDE IONS: The azide ions are inorganic impurities derived from metal azide v. SARTAN CATALYST: Catalyst mainly consist of sulfur containing agent or metal catalyst which decomposes carcinogenic azido impurities into non carcinogenic amine derivatives. Sulfur containing agents represented sodium dithionite, Sodium metabisulfite, sodium bisulfite, sodium sulfide, whereas metal catalyst containing agents represented by Raney Ni/H2, Pd/C/H2, Raney Ni/H2 and the like or mixture thereof which can perform the same function

SUMMARY OF THE INVENTION

Disclosed herein is an improved and safe process for the preparation of sartans particularly Losartan and its pharmaceutically acceptable salt preferably potassium salt. Disclosed herein is an improved and efficient process to alleviate or to minimise the azido impurity particularly Losartan azido of Formula III content irreversibly and in some instances, present in undetectable levels or within the pharmaceutically acceptable limits in drug class called as SARTANS, particularly LOSARTAN and its salts preferably POTASSIUM salt. Inventors of the present invention have achieved elimination/alleviation (or minimization) of azido content by incorporating the use of “SARTAN CATALYST” during the workup of the reaction mass, wherein said “Sartan catalyst is sulfur containing agents or metal catalyst, “sartan catalyst” decomposes the carcinogenic azido impurity into corresponding non-carcinogenic amine derivative which form water soluble salts with acid and gets removed during standard process of isolation of losartan of Formula I or if present within pharmaceutically acceptable limit.

The present invention (Scheme 3) discloses an improved process for the preparation of Losartan and its salts there of preferably potassium salt comprising reaction of Aq. Solution of Losartan sodium (Formula V) with “sartan catalyst” to decompose azido impurities into corresponding amine derivatives and the pH of the reaction mass is adjusted to about 3-4 with acid preferably HC1 to convert said amine derivatives into water soluble salt and hydrolysis of Losartan sodium to obtain Losartan of Formula I free from all azido impurity and if present within pharmaceutically acceptable limit. Losartan free from Losartan azido impurity is then further converted into its potassium salt by standard method known in the prior art.

Scheme-3

Sartan catalyst” is featured by the fact that it mainly consists of sulfur containing or metal catalyst reducing agent which decomposes carcinogenic azido impurities into corresponding non-carcinogenic amine derivatives which in salt form being water soluble gets removed during standard work up as described herein before. “Sartan catalyst is selected from the group comprising sulfur containing agents or metal catalyst. Sulfur containing agent is selected from the group comprising sodium dithionite, sodium metabisulfite, sodium bisulfite, sodium sulfide or mixture thereof. Metal catalyst is selected from the group comprising Raney Ni/Fh, Pd/C/H2, Pt/C/H2 and the like or mixture thereof which can perform the same function and said sartan catalyst is capable of decomposing carcinogenic azido impurities into corresponding non- carcinogenic amine derivatives which as described herein before are washed away during the isolation of Losartan of Formula I.

DETAILED DESCREPTION OF THE INVENTION:

Much attention and effort has been applied in recent years towards the elimination (or minimization) of nitrosamine impurities from the pharmaceutical products with special reference to class of SARTAN drugs. There has not been any disclosure in the prior art which pertains to alleviate or minimize carcinogenic azido impurities like Losartan azido impurities.

However, inventors of the present invention disclose herein an efficient process for the preparation of sartans preferably Losartan and its potassium salt of Formulae I and II respectively either free of azido impurities or if present then within pharmaceutically acceptable limit.

The preferred embodiments described herein details for illustrative purposes only and are by no means limiting and can be further enhanced by many variations. It is understood that various omissions and substitutions of equivalents are contemplated as circumstances may suggest or render expedient but are intended to cover the application or implementation without departing from the spirit or scope of the present invention.

With detailed reference to certain embodiments of the present invention, the example of these embodiments illustrates with structure and the formula enclosed. Although the present invention will be illustrated in conjunction with row illustrated embodiments, but it is to be understood that they are not intended to limit the invention to those embodiments. On the contrary, it is contemplated that contain all alternative forms, modification and the equivalents that may be included in the scope of the invention as defined in the claims. The invention is not restricted to method described herein and material, but include any method similar or equivalent with method described herein and material that can be used for putting into practice the present invention and material. One or more in the list of references being incorporated to, patent or similar data is different from the application (including but not limited to defined term, term usage, described technology etc. or runs counter to the application, it is as the criteria with the application.

Along with the main aspect of the invention as discussed herein; all other aspects of the present invention are discussed herein after in detail via different embodiments.

The essence of the present invention lies in the process of alleviation or minimization of the azido impurities from the class of sartan drugs particularly Losartan and its pharmaceutically acceptable salts comprising incorporating sulphur containing reducing agent or metal catalyst reducing agent herein referred as sartan catalyst which decomposes carcinogenic azido impurities into corresponding non carcinogenic amine derivatives which as described herein before gets removed during standard purification and isolation process.

There is no teaching or motivation to a person skilled in the art to use sartan catalyst to completely remove or minimize up to pharmaceutically acceptable limit of azido impurities from the class of sartan drugs specifically Losartan and its potassium salt free or having said azido impurities within pharmaceutically acceptable limit.

Inventors of the present invention have been able to achieve this and as a result; disclose herein an efficient process as depicted herein below in Scheme-2 for the preparation of sartans preferably Losartan potassium free of Losartan azido impurity or if present then within pharmaceutically acceptable limit.

Scheme-2 um

Losartan cyanoalcohol as shown in scheme 2 can be procured from the process as known in the art and is as represented in Scheme-4.

Scheme-4

Scheme 4

The azido impurities profile including Losartan azido in Losartan of Formula I and its potassium salt of Formula II based on conventional process of prior art against the improved process of present invention is given herein below in:

Table-1: A comparison of azido impurity profile in Conventional Process Vs Modified process for the preparation of Losartan of formula I

Table 2: A comparison of azido impurity profile in Conventional Process Vs Modified process for the preparation of Losartan Potassium of Formula II (Final API)

Conventional process means the process of prior art where “sartan catalyst” is not used and modified process refers to the process of the present invention where “sartan catalyst” is used to make azido free sartan molecule. Table- 1 herein above depict details of azido impurities based on prior art conventional process versus the improved and efficient process disclosed herein and referred as modified process wherein the sartan catalyst has been used. Azido impurities based on the conventional process for the preparation of losartan of formula I are present in the range of 1-50 ppm and that of losartan azido of formula III is present in the range of 50-150 ppm. However, Losartan molecule of Formula I obtained based on modified process using sartan catalyst except losartan azido all impurities are absent. Even losartan azido impurity is also present less than 0.3 ppm which is about 5000 times less compared to conventional process.

Similarly, Table-2 describes comparative azido impurities including losartan azido based on conventional process and modified process in losartan potassium salt. Based on conventional process the azido impurities are present in the range of 1-150 ppm and losartan azido impurity in the range of 50-150 ppm. However, the losartan potassium salt based on the modified process wherein sartan catalyst has been used the azido impurities are absent and losartan azido impurity if present is less than 0.3 ppm which is 5000 time less compared to conventional process and also much less than pharmaceutically acceptable limit of 10 ppm.

From foregoing it is evident that the process of the present invention comprising the use of sartan catalyst give Losartan, wherein Losartan azido impurity is present to a level of less than 0.3 ppm which is within pharmaceutically acceptable limit. It is evident from Table- 1 herein above that content of the Losartan azido impurity gets drastically reduced by nearly about 5000 times over the conventional process, thereby making the process of present invention novel and inventive.

Table-2 also indicates that in Losartan potassium salt synthesized from Losartan, all other azido impurities are not detectable so absent and the Losartan azido too is generally undetectable but some time it is present less than 0.3 ppm which is within the acceptable level compared to 150 ppm when sartan catalyst is not used.

Foregoing herein before proves that the use of “sartan catalyst’ has the capability of decomposing carcinogenic azido impurities into corresponding non-carcinogenic amine derivatives which gets removed during standard process of isolation as described herein before to obtain azido impurity free losartan and if present then only up to less than 0.3 ppm against the standard pharmaceutically allowed limit of 10 ppm.

Use of sartan catalyst for the preparation of sartan molecule has not been disclosed in the prior art.

In a general embodiment of the present invention, Losartan cyanoalcohol of Formula IV is treated with metal azide in presence of tertiary amine salt resulting into formation of Losartan which is further treated with a aqueous alkali metal hydroxide solution to obtain alkali metal salt (preferably sodium) of Losartan. To the aqueous solution of alkali metal salt of Losartan is then added a “sartan catalyst” followed by heating till azido impurities are reduced to a remarkable extent as the said azido impurities including losartan azido impurity gets converted into corresponding non-carcinogenic amine derivatives. The aq. Solution of alkali metal salt of Losartan containing said amine derivatives is then treated with acid convert as described herein before to convert said amine derivatives into corresponding water soluble amine salts and also hydrolysis of alkali metal salt of losartan into losartan of Formula I. Amine salts which being water soluble gets removed during standard process of isolation of Losartan of Formula I either free from azido impurity and if present then it is less than 0.3ppm which is far less than pharmaceutically acceptable limit of 10 ppm. This Losartan with controlled azido impurities is then further treated with potassium hydroxide to obtain Losartan potassium of Formula II either free from all azido impurity or impurity present to a level of less than 0.3 ppm which is far less than pharmaceutically acceptable limit of 10 ppm.

Acid used for pH adjustment is selected from the group comprising HC1, acetic acid, sulfuric acid or mixture thereof

Alkali metal hydroxide is selected from the group comprising sodium hydroxide.

“Sartan catalyst is selected from the group comprising sulfur containing agents or metal catalyst. Sulfur containing agent is selected from the group comprising sodium dithionite, sodium metabisulfite, sodium bisulfite, sodium sulfide or mixture thereof

.Metal catalyst is selected from the group comprising Raney Ni/Fh, Pd/C/H2, Pt/C/Eh and the like or mixture thereof which can perform the same function and said sartan catalyst is capable of decomposing carcinogenic azido impurities into non-carcinogenic amine derivatives which are washed away either during the isolation of crude Losartan at acidic pH (3-4) or preparation of final API.

In a specific embodiment of the present invention Losartan cyanoalcohol of Formula IV is treated with sodium azide in presence of triethylamine hydrochloride resulting into formation of Losartan of Formula I which is further treated with a sodium hydroxide to form sodium salt of Losartan of Formula V. The aqueous solution of Sodium salt of Losartan of Formula V is then contacted with a “sartan catalyst at about 80-90 °C for about 2-4 h so that azido impurities including Losartan azido impurity of Formula III is completely decomposed into corresponding amine derivatives. This aqueous solution of Losartan sodium with controlled azido impurities and said amine derivatives is then further contacted with Hydrochloric acid as described herein before hydrolyze Losartan sodium to free Losartan and also to convert said amine derivatives into corresponding water soluble salts which gets removed during the standard work up to obtain Losartan having Losartan azido impurity less than 0.3 ppm. Finally, Losartan is treated with potassium hydroxide to obtain Losartan potassium where in all azido impurities are absent and if present then only losartan azido impurity of Formula III less than 0.3 ppm which is far less than pharmaceutically acceptable limit of 10 ppm.

The invention can be best understood by the illustrative non-limiting examples:

Example 1: Preparation of Losartan using sartan catalyst (Sulfur containing)

To a stirred solution of Losartan cyano alcohol (120 g) in toluene (360 mL), sodium azide (54 g,) was added followed by addition of triethylamine hydrochloride (125 g). Reaction mass was heated to 95-100 °C and maintained till reaction complies. Aq. NaOH solution was added to the reaction mass and three layers were separated. Product layer was diluted with water (360 mL) and to the reaction mass sartan catalyst (0.05 w/w) was added. Reaction mass was heated to 80- 90 °C and maintained to reduce azido impurity. Reaction mass was cool and pH of reaction mass was adjusted to get Losartan free from all azido impurity or azido impurity well within pharmaceutically acceptable limit (0.3 ppm).

Example 2: Preparation of Losartan using sartan catalyst (Metal catalyst)

To a stirred solution of Losartan cyano alcohol (120 g) in toluene (360 mL), sodium azide (54 g,) was added followed by addition of triethylamine hydrochloride (125 g). Reaction mass was heated to 95-100 °C and maintained till reaction complies. Aq. NaOH solution was added to the reaction mass and three layers were separated. Product layer was diluted with water (360 mL) and to the reaction mass sartan catalyst (0.01-0.05 w/w) was added. Reaction mass was maintained to 25-30 °C to reduce azido impurity. The pH of reaction mass was adjusted to 3-4 to isolate Losartan free from all azido impurity or well within pharmaceutically acceptable limit (0.3 ppm)

Example 3: Preparation of Losartan Potassium using Losartan prepared in example 1 or 2

To a stirred solution of Losartan prepared by above process (100 g) in Isopropyl alcohol (700 mL) was added a solution of KOH (15 g) in isopropyl alcohol (300 mL) at 25-35 °C. Isopropyl alcohol was distilled out completely under vacuum, degas and stripped out with 100 mL methyl ethyl ketone. To the residue methyl ethyl ketone was added, reaction mass was refluxed, cool, and centrifuged to get pure Losartan Potassium with all azido impurities well within pharmaceutical acceptable limit (NMT 0.3 ppm).

Contacting herein means reacting, mixing, refluxing, adding and the likes

Decomposition of azido impurities is also referred as removed and the like herein

Claims

CLAIMS,

1.A process for the preparation of compound of Formula-I having azido set of impurity/ies within pharmaceutically acceptable limits

Formula-I Formula-V

Comprising a) contacting the aqueous solution of Losartan sodium salt of Formula V with sartan catalyst to remove azido impurities up to pharmaceutically acceptable limit ; b) contacting aq. Solution of Losartan sodium salt after sartan catalyst treatment (claim la) with an acid to obtain substantially pure Losartan of Formula I free of azido or containing azido impurities within pharmaceutically acceptable limit.

2. The process as claimed in claim 1 wherein sartan catalyst is selected from the group comprising sulfur containing agents or metal catalyst or mixture thereof.

3. The process as claimed in claim 2 wherein sulfur containing agent is selected from the group comprising sodium dithionite, sodium metabisulfite, sodium bisulfite, sodium sulfide or mixture thereof.

4. The process as claimed in claim 2 wherein metal catalyst is selected from the group comprising Raney Ni/Fh, Pd/C/FL, Pt/C/FL and the like or mixture thereof .

5. The process as claimed in claim 1 wherein the substantially pure losartan obtained in claim 1 is contacted with potassium hydroxide to obtain azido impurities free or containing said azido impurities within pharmaceutically acceptable limit Losartan potassium of formula II.