This invention relates to a novel and inventive process for the preparation of class of sartan drug molecule of Formula I having nil or minimised nitrosamine impurities within pharmaceutically acceptable level.
Particularly, this invention discloses an improved safe process for the preparation of sartan drugs of Formula I

Formula I
Wherein R is selected from group comprising:

BACKGROUND OF THE INVENTION:
N-NITROSO COMPOUNDS: THE HISTORICAL PERSPECTIVE:
In 1874, the German chemist Otto N. Witt reacted nitrous acid and its ethers with secondary and tertiary amines and the resultant product obtained was named as “nitrosamine”. This class of chemical compound comprises a nitrosyl group “-NO” connected to an amine.
The majority of N-nitroso compounds are carcinogenic in nature and are formed when an amine reacts with a nitrosating agent such as nitrous acid, nitrosyl species, nitrogen oxides, and nitrite salts, etc. There are three major types of nitroso compound, viz., N-nitrosamines, N-nitrosamides, and N-nitrosoureas, that are formed when nitrosating agents react with amines, amides, and ureas respectively.
Nitroso compounds of particular interest for the present invention are alkyl nitrosoamines which have been identified as carcinogens for a wide range of mamalian species. Nitroso-amines have been detected in many kinds of products such as pharmaceuticals, pesticides, cutting oils, cigarette smoke and foods like cheese, fish spices, etc.
The formation of nitrosamines is generally possible when secondary or tertiary amines reacts with nitrous acid. Nitrous acid itself is unstable but gets formed in situ from nitrites (NO2) under acid conditions. API manufacturing process under the presence of secondary or tertiary amines and nitrites (as in case of sartans) results into the generation of nitrosamine compounds. Some drug products may also degrade during storage, resulting in the formation of nitrosamines (e.g., ranitidine) - Excipients or container-closure system may contain amines and potential sources of nitrosating agent (e.g., metformin).
Formation of potential carcinogenic nitrosamine impurities is depicted herein below:

Wherein; secondary amine when comes in contact with nitrous acid it results in the formation of nitrosamine.
As per the current information available, FDA database shows that >1400 product lots have been recalled from the market due to the presence of carcinogenic N-nitrosamine impurities at levels beyond the acceptable intake limit. The drugs where the said impurities were present in recalled products included valsartan, irbesartan, losartan, metformin, ranitidine, and nizatidine. This perspective provides a critical account of these product recalls with an emphasis on the source and mechanism for the formation of N-nitrosamines in these products.
Medicine Regulatory Authorities first became aware of the presence of the nitrosamine impurity, nitrosodimethylamine (NDMA), in products like valsartan in July 2018. Valsartan is an Angiotensin II Receptor Blocker (ARB) and belongs to a family of analogue compounds commonly referred to as the sartans.
Since July 2018, the pharmacological class of “sartans” have been the subject of considerable media and analytical interest, as it became known that they are contaminated with nitrosamines such as N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) and N-nitrosodiisopropylamine (NDIPA), N -nitrosoethylisopropylamine (NEIPA) and N -nitroso-N-methyl-4-aminobutyric acid (NMBA).
The highest number of product recalls (~24% of the total) is associated with losartan, with 324 lots containing the said nitrosamine impurity recalled from the market. This is followed by products like metformin, valsartan, and irbesartan which accounted for ~19%, ~17%, and ~3.0% of drug recalls, respectively, due to undesired levels of nitrosamines in these products.
A careful analysis of the FDA database reveals that ~81% of the recalls are drug products containing “sartans”. In the case of the sartan compounds, most of them contain a tetrazole ring and formation of this tetrazole ring employs the use of sodium azide which in turn contains sodium nitrite (as an impurity) and the investigation revealed that the sodium nitrite is the cause for the formation of nitrosamine impurities.
Coincidently the solvents those employed either were amines, or contained traces of amines, and this likely afforded the observed NDMA and NDEA impurities.
As per available sources interim allowable daily intake limits for N-nitrosamine impurities is as given in TABLE 1:
TABLE-I
Chemical name Abbreviation Allowable Daily Intake
N-nitrosodimethylamine NDMA 96.0 ng/day
N-nitrosodiethylamine NDEA 26.5 ng/day
N-nitroso-N-methyl-4-aminobutyric acid NMBA 96.0 ng/day
N-nitrosodiisopropylamine DIPNA 26.5 ng/day
N-nitrosoethylisopropylamine EIPNA 26.5 ng/day
Interim limits for NDMA, NDEA and NMBA in Angiotensin II receptors Blockers (ARBs) is as given in TABLE 2:
As per the information available:

Drug Max daily dose(mg/day) Acceptable intake (NDMA) (ng/day)* Acceptable intake (NDMA) (ppm)** Acceptable intake (NDEA) (ng/day)* Acceptable intake (NDEA) (ppm)** Acceptable intake (NMBA) (ng/day)* Acceptable intake (NMBA) (ppm)**
Valsartan 320 96 0.3 26.5 0.083 96 0.3
Losartan 100 96 0.96 26.5 0.27 96 0.96***
Irbesartan 300 96 0.32 26.5 0.088 96 0.32
Azilsartan 80 96 1.2 26.5 0.33 96 1.2
Olmesartan 40 96 2.4 26.5 0.66 96 2.4
Eprosartan 800 96 0.12 26.5 0.033 96 0.12
Candesartan 32 96 3.0 26.5 0.83 96 3.0
Telmisartan 80 96 1.2 26.5 0.33 96 1.2

* The acceptable intake is a daily exposure to a compound such as NDMA, NDEA, or NMBA that approximates a 1:100,000 cancer risk after 70 years exposure
** These values are based on a drug's maximum daily dose as reflected in the drug label
*** FDA is temporarily not objecting to losartan with NMBA below 9.82 ppm remaining on the market
Although nitrosamine impurities have been found in only some drug products, and batches of those products have been recalled when there were unacceptable levels of these impurities, nitrosamine impurities might exist in other APIs and drug products due to use of vulnerable processes and materials that may produce nitrosamine impurities.
Nitrites used as reagents in the preparation of one of the key raw materials (sodium azide)gets carried over into subsequent steps, despite purification operations, and these nitrites react with secondary or tertiary amines to generate nitrosamine impurities.
Therefore, whenever nitrite salts are present, carryover into subsequent steps cannot be ruled out. In general, processes that use nitrites in the presence of secondary, tertiary, or quaternary amines at acidic pH are at risk of generating nitrosamine impurities.
Another potential source of formation of nitrosamine impurities is lack of optimization of the manufacturing process for APIs when intermediates or solvents are inappropriate or poorly controlled.
Valsartan represented by formula II was first reported by Novartis in US5399578 (hereinafter referred as “578). ‘578 discloses two routes for the preparation as illustrated herein below (Scheme-1 and scheme -2 respectively):
Route-1:

Scheme-1
Drawback associated with this method is that, it involves a greater number of steps from bromo-OTBN to compound-04 further; it comprises the use of hazardous and toxic chemical oxalyl chloride.
Route-2

Scheme-2
Route-2 (Scheme-2) involves protection and de-protection steps, which makes process lengthy. Also require hydrogenation for the hydrolysis of benzyl group, which is a limitation on production capacity.

The most commonly commercial route based on Route-1 of Novartis is as Scheme-3 illustrated herein below:
Route-3:

Scheme-3
During the conversion of an ester represented as compound-6 into alkali metal salt of valsartan represented as compound-7 being soluble in water remains in aqueous reaction mass along with excess of sodium azide (being carried forward from previous step) and hence contains traces of sodium nitrite (as unreacted starting material in sodium azide). The said aqueous reaction mass containing sodium salt (compound-7) is then subjected to the neutralization using hydrochloric acid. During neutralisation, nitrous acid is produced, which forms nitrosamine impurity. Furthermore, neutralization of unreacted sodium azide being carried forward generates explosive hydrazoic acid.

Thus, the drawback associated with this scheme is the use of reagents like tertiary amines, dimethylformamide (both are contributing factors towards the formation of the nitrosamine impurities) and sodium azide which also contains sodium nitrite as an impurity, are root causes for nitrosamine impurity formation. It also produces highly explosive hydrazoic acid (by product) thereby making the process risky and unsafe.

Probable sources for nitrosable substances in process of preparation of valsartan as per Scheme-3 are illustrated herein below:
a. Preparation of L-valine methyl ester hydrochloride: L-valine methyl ester hydrochloride is prepared by reaction of L-valine with thionyl chloride in methanol as solvent in presence of catalytic amount of N,N-dimethyl formamide (DMF) is illustrated in Scheme-4.

Scheme-4
b. Preparation of valeryl chloride: Valeryl chloride also prepared by the reaction of Valeric acid with thionyl chloride in presence of catalytic N,N-dimethyl formamide (DMF) is illustrated in Scheme-5.

Scheme-5
c. Preparation of compound-5: Literature reveals that, Acylation of compound-4 with valeryl chloride was carried out in dichloromethane using tertiary amines trimethylamine or di-isopropyl amines etc. is illustrated in Scheme-6.

Scheme-6
d. Preparation of compound-6: Hydrolysis of methyl ester is carried out in biphasic medium and quaternary ammonium salt being used as phase transfer catalyst for the same is illustrated in Scheme-7. This is also a potential nitrosable substance.

Scheme-7
Here, it is to be noted that DMF, tertiary amines or quaternary amines used therein are the potential amino substances in the process for the preparation of valsartan.

SOURCE OF NITROSATING AGENTS: Nitrates are important nitrosating agents, as they produce nitrous acid when it reacts with acid and nitrous acid is responsible for formation of nitrosamine impurities.

SODIUM AZIDE PREPARATION: Sodium azide is prepared comprising using sodium nitrite as depicted herein below:

Sodium azide thus formed contains traces of unreacted sodium nitrite, and hence it becomes potential source for the formation of nitrosamine impurities and therefore sodium azide is potential source for nitrosating agent in process of preparation of valsartan along with other sartans having tetrazole ring as a part of their structure.
Furthermore; sodium azide being carry forwarded during the synthesis produces explosive hydrazoic acid on treatment with hydrochloric acid thereby making the said process unsafe.

In view of drawbacks described herein before, there is a dire need for an efficient and improved process for the preparation of sartan drug molecule of Formula I eliminating or minimising to acceptable limit of N-nitrosamines, particularly N,N-dialkyl-N-nitrosamines and N-alkyl-N-aryl-N-nitrosamines as impurities in the final drug molecule. N,N-dimethylnitrosamine, for example, has a LD50 of only 10 mg/Kg is of greater significance than their toxicity; however, are potential carcinogenic, mutagenic, and teratogenic effects. Many; if not, most N-nitrosamines, are classified as animal carcinogens by OSHA.
Because of the aforementioned deleterious health-related effects, stringent limitations have been placed upon the permissible amounts of N-nitrosamine impurities in consumer products such as cosmetics, pharmaceuticals, pesticides, dyes and pigments.

TECHNICAL PROBLEMS ASSOCIATED WITH THE PRIOR ART:
The most prominent shortcoming associated with process for the preparation of sartan drug molecule particularly valsartan disclosed therein in the prior art is the conversion of water soluble and unisolable in solid form sodium salt of sartan to free sartan base particularly valsartan by treatment with hydrochloric acid. During this process, residual sodium nitrite present in sodium azide generates nitrous acid. As nitrous acid is known to produce nitrosamine compounds by reacting with secondary amines, there is always a possibility of generation of various nitrosamine impurities depending on secondary amine used in addition to formation of sartan drugs of formula-I .
Processes disclosed therein in the prior art for the preparation of valsartan comprises isolation of valsartan from corresponding water soluble sodium salt comprising neutralising said sodium salt using aqueous hydrochloric acid, wherein sodium salt of valsartan being water soluble remains in aqueous reaction mass along unreacted sodium azide that is used for the tetrazole ring formation during the synthesis of sartan drug molecule of Formula I particularly Valsartan of Formula II. Unreacted sodium azide also carries along with it traces of sodium nitrite (usually present in unreacted sodium azide). This aqueous reaction mass is further neutralised with aqueous hydrochloric acid which results into generation of nitrous acid which forms nitrosamine impurity as disclosed herein before. As evident from foregoing studies, the reason for formation of unwanted nitrosamine impurity is the use of Aq. HCl during the hydrolysis of sodium salt of valsartan also containing unreacted sodium azide (hence sodium nitrite). This sodium nitrite being carried forward by unreacted sodium azide generates nitrosating group responsible for nitrosamine impurity.

TECHNICAL SOLUTION:
In view of 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 pharmaceutical acceptable limit of nitrosamine impurities.
Inventors of the present invention based on their expertise and R&D activity found that conversion of water soluble sodium salt which can’t be isolated in solid form from the aq. reaction mass into corresponding alkaline earth metal salt of valsartan which being insoluble in water gets precipitated in solid form from the reaction mass leaving behind sodium azide with traces of sodium nitrite which remains in the mother liquor. This appreciable noble and inventive modification in the process internsolve all problems associated with the prior art process. According to inventors of the present invention alkaline earth metal salt such as calcium salt and the like of sartan molecule of Formula I particularly of valsartan molecule of Formula II being insoluble in water is isolated in solid form and washed with water to make the said alkaline earth metal salt of sartan drug free of sodium azide thereby eliminating the chance of free sodium azide and hence free of sodium nitrite which acts as nitrosating source for nitrosamine impurity. This eliminates the possibility of formation of undesired nitrosoamine impurity thereby making available nitrosoamine free sartan drug molecule of Formula I particularly Valsartan of Formula II.
There is no indication or teaching which motivates a person skilled in the art to propose a process where the formation of said toxic nitrosamine impurities is either eliminated or minimised to pharmaceutically acceptable limit. Inventors of the present invention based on their exhaustive R&D activity have successfully developed an efficient and safe process to obtain sartan molecule of Formula I particularly valsartan of Formula II free of nitrosamine impurity.
As evident from foregoing, the inventors of the present invention disclose herein a novel and inventive process represented by Scheme-8 for the preparation of sartan drug molecule of Formula I particularly valsartan molecule of Formula II and said novel and improved process either eliminates or minimises the nitrosamine impurity(ies) to pharmaceutically acceptable limit.

SCHEME-8

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. For the disclosure “NITROSAMINES” (or more formally N-Nitrosamines) are organic compounds of the chemical structure R2N-N=O, where R is usually an alkyl group. They feature a nitroso group (NO+) bonded to a deprotonated amine.
The organic chemistry of nitrosamines is well developed with regard to their syntheses, their structures, and their reactions. They usually are produced by the reaction of nitrous acid (HNO2) and secondary amines.
HONO + R2NH ? R2N-NO + H2O
The nitrous acid usually arises from protonation of a nitrite. This synthesis method is relevant to the generation of nitrosamines under some biological conditions.
iv. PRODUCT RECALLS: A product recall is defined as a request to return, exchange, or replace a product after a manufacturer or consumer watch group discovers defects that could hinder performance, harm consumers, or produce legal issues for the producers.
v. LD50: LD50 is an acronym which stands for Lethal Dose 50. It is a measure of the amount of a substance that is needed to kill half of a test population of animals. It is used to measure the acute toxicity of substances, and this type of testing is normally performed with rats and mice.

OBJECTS OF THE INVENTION: The present invention provides an improved, safe, novel and non-obvious inventive process for controlling i.e. eliminating or minimizing the formation of Nitrosamine impurities in the class of the drugs called as “SARTANS”.

One of the aspects of the present invention is to provide a process for the minimization or limiting nitrosamine impurity to pharmaceutically acceptable limit in the class of the drugs called as “SARTANS”.

One of the aspects of the present invention to provide a process for the preparation of SARTANS preferably VALSARTAN free from nitrosamine impurity(ies).

One of the aspects of the present invention is to provide a process for the preparation of SARTANS preferably VALSARTAN to minimise nitrosamine impurity(ies) within pharmaceutically acceptable limits.

One of the aspects of the present invention is to avoid the formation of nitrosamines during the neutralisation of sodium salt of valsartan thereby avoiding the probability of free existence of nitrosating group.

One of the aspects of the present invention is to replace water soluble hence unisolable sodium salt of valsartan by isolable, water insoluble alkaline earth metal salt of valsartan for the neutralisation of said salt with mineral acid to obtain nitrosoamine free valsartan molecule.

One of the aspects of the present invention is to enable the efficiency of production of Sartans particularly valsartan by converting water soluble and unisolable in solid form sodium salt of sartan from the aq. reaction mass itself to water insoluble thus isolable in solid form from aq. reaction mass alkaline earth metal salt of sartan by treating the reaction mass containing said sodium salt with alkaline earth metal salt as such or in solution form to eliminate possibility of formation of nitrosating agent thus giving nitrosoamine free sartan.

One more aspects of the present invention is to enable the efficiency of production of Sartans particularly valsartan by converting water soluble and unisolable in solid form sodium salt of valsartan to alkaline earth metal salt of valsartan to react with hydrochloric acid in presence of a solvent followed by its extraction to eliminate possibility of presence of nitrosating agent if any.

One of the aspects of the present invention is to develop a process that comprises replacement of sodium salt of valsartan by alkaline earth metal salt of valsartan for the preparation of sartan particularly valsartan.

One of the aspects of the present invention is to develop a process that comprises easy isolation of calcium salt of valsartan as insoluble and isolable in solid form from aq. reaction medium and washable with water to make it free from nitrosoamine impurity forming contaminants from the aq. reaction.

One of the aspects of the present invention is to develop a safe process that avoids the formation explosive hydrazoic acid.

SUMMARY OF THE INVENTION:
Disclosed herein is an improved and safe process for the preparation of sartans of Formula I particularly Valsartan of Formula II. Disclosed herein is an innovative process which is directed to develop an improved and efficient process to eliminate or to minimise nitrosamine content irreversibly and in some instances to undetectable levels in drug class called as SARTANS of Formula I, particularly Valsartan of Formula II. t) as mentioned herein above thereby making the process safe and commercially viable.
Process of the present invention comprises conversion of water soluble sodium salt of sartan drug molecule of Formula I particularly valsartan of Formula II into corresponding water insoluble alkaline earth metal salt which being insoluble in water gets separated in solid form from the reaction mass thereby eliminating the possibility of carryover of nitrosating agents like sodium azide responsible for the formation of nitrosamine impurities which remains in the mother liquor of the reaction mass. Any contaminant, if any with the precipitated alkaline earth metal salt gets removed during water washing of the isolated alkaline earth metal salt of the sartan drug molecule of Formula I particularly valsartan of Formula II, thereby eliminating the possibility of formation of nitrosoamine impurity.

Formula II
Present invention is further characterised by the feature that neutralisation of unreacted sodium azide being used in tetrazole ring formation is avoided as it is left behind in the residual reaction mass from which the alkaline earth metal salt of the sartan drug gets precipitated and sodium azide is not carried forward along with the alkaline earth metal salt of sartan drug molecule which is then neutralised to obtain sartan drug molecule. As the said alkaline earth metal salt which is neutralised using an acid is free of sodium azide, thereby avoiding the formation of hazardous and explosive hydrazoic acid.

General formula Sartan class of drugs R from General formula I Specific Sartan

Formula I
wherein R is selected from:

Valsartan


Losartan


Irbesartan


Olmesartan


Candesartan

DETAILED DECRIPTION OF THE INVENTION:
Much attention and effort has been applied in recent years towards the elimination (or minimization) of nitrosamine impurities from the pharmaceutical produces with special reference to class of SARTAN drugs. Inventors of the present invention have been able to achieve this and as a result; disclose herein an efficient process for the preparation of sartans of Formula I preferably valsartan of Formula II free of nitrosoamine impurity or containing pharmaceutically acceptable limit of the said nitrosoamine impurities.

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 conversion of unisolablein solid form from aq. Reaction mass water soluble sodium salt into corresponding water insoluble isolablein solid form from aq. Reaction mass alkaline earth metal salt of sartans preferably calcium salt which being insoluble in water precipitates and is isolated in solid form. The said alkaline earth metal solid is filtered and washed repeatedly with water to make it free from any impurity particularly azide usually being carried forward from the reaction mass which primarily is responsible for the formation of nitrosoamine impurity(ies); when comes in contact with an acid. The said alkaline earth metal salt free of azide is hydrolysed with an acid preferably HCl to give sartan drug molecule particularly valsartan free of nitrosoamine impurity. There is no teaching or motivation to a person skilled in the art to convert water soluble alkali metal salt like sodium salt of sartan molecule into corresponding alkaline earth metal salt and isolate said alkaline earth metal sartan salt particularly alkaline earth metal salt of Valsartan in solid form thereby replacing water soluble and unisolable sodium valsartan and make it free of azide impurity which remains in mother liquor and to obtain sartan particularly valsartan free of said unwanted nitrosoamine impurity.
The innovative process is illustrated herein below in SCHEME -8:

SCHEME-8
However, complete chemical sequence for the preparation if valsartan is illustrated herein below as SCHEME -9:

SCHEME-9
2-(4'-Bromomethylphenyl)benzonitrile (Bromo-OTBN) (compound-1) to (S)-Methyl 2-(((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)amino)-3-methylbutanoate hydrochloride (compound-3):

(S)-Methyl 2-(((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)amino)-3-methylbutanoate hydrochloride (compound-3) to N-[(2'-Cyano[1,1'-biphenyl]-4-yl)methyl]-N-(1-oxopentyl)-L-valine methyl ester (compound-5)

N-[(2'-Cyano[1,1'-biphenyl]-4-yl)methyl]-N-(1-oxopentyl)-L-valine methyl ester (compound-5) to N-(1-Oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine Methyl Ester (compound-6)

N-(1-Oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine Methyl Ester (compound 6) to Valsartan sodium salt (compound-7)

Valsartan sodium salt (compound-7) to valsartan calcium salt (compound-8)

Valsartan calcium salt (compound-8) to valsartan.

Key raw materials and key intermediates up tillcompound-7could be prepared either from the processes disclosed in the prior art or modified ones as illustrated herein in in the examples.

In a general embodiment of the present invention, sartan of Formula I is prepared as per the SCHEME-10 as given herein below:

M= Alkaline earth metal
SCHEME-10
Wherein, the water soluble sodium salt of sartan represented by formula E is treated with salt of alkaline earth metal to obtain corresponding alkaline earth metal salt of sartan represented by formula F, which being water insoluble precipitates in solid form and said precipitated salt isolated in solid form is washed with water to free it from nitrosoable impurities. Water insoluble and isolable alkaline earth metal salt of sartan of formula F is collected and suspended in water hydrolysed by the pH adjustment with mineral acid. Desired sartan is further isolated by method known in the literature.

Alkaline earth metal salt is selected from salts of strong acid and weak base preferably calcium chloride.

Solvent/organic solvent used in the said embodiment is selected from the group comprising water immiscible solvents selected from the group comprising methylene dichloride, ethylene dichloride, ethyl acetate and the like preferably methylene dichloride
The acid used for pH adjustment is selected from the group of mineral acids preferably HCl.

In another general embodiment of the present invention Valsartan is prepared as per the SCHEME-11 as given herein below:

SCHEME-11

Wherein, the water soluble alkali metal salt of valsartan is contacted with salt of alkaline earth metal resulting into formation of corresponding water insoluble isolable from aq. Water reaction mass and washable with water to remove nitrosable contaminant from aq. Reaction mass, alkaline earth metal salt of valsartan. Water insoluble and isolable alkaline earth metal salt of valsartan is collected and suspended in water and hydrolysed by the addition of acid for pH adjustment. Desired valsartan is extracted in the said organic solvent. Solvent is removed by the distillation and crystallised from organic solvent.

Alkaline earth metal salt is selected from salts of strong acid and weak base preferably calcium chloride.

Solvent/organic solvent used in the said embodiment is selected from the group comprising water immiscible solvent selected from the group comprising methylene dichloride, ethylene dichloride, ethyl acetate and the like preferably methylene dichloride.

The acid used for pH adjustment is selected from the group of mineral acids preferable HCl.
In a specific and preferred embodiment Valsartan is prepared by the sequence disclosed SCHEME-8.

SCHEME-8
Wherein, water soluble sodium salt of valsartan represented by compound-7 is treated further with calcium salt preferably calcium chloride resulting into formation of water insoluble isolable in solid form from aqueous medium calcium salt of valsartan represented by compound -8.Water insoluble and isolable calcium salt of valsartan of formula compound-8 is collected and suspended in water and an organic solvent preferably methylene dichloride is added followed by the pH adjustment using mineral acid preferably Aq. HCl. Desired valsartan is extracted in the methylene dichloride. Methylene dichloride is removed by the distillation to obtain crude valsartan which is crystallised from ethyl acetate to obtain substantially pure valsartan free of nitrosoamine impurity.

In another embodiment Valsartan is prepared by the sequence disclosed in SCHEME-8.

Wherein, water soluble sodium salt of valsartan represented by compound-7 is treated further with calcium salt preferably calcium chloride resulting into formation of isolable in solid form from aqueous medium as calcium salt of valsartan represented by compound -8.Water insoluble and isolable calcium salt of valsartan of formula compound-8 is collected by filtration followed by washing with water to remove unwanted impurities. Solid calcium valsartan salt is then treated with hydrochloric acid to get desired valsartan either free from or with minimised pharmaceutically acceptable nitrosamine impurities.

The invention is best understood from the comparative table as illustrated herein below which validated the fact that when water soluble unisolable in solid form from aq. Reaction mass sodium salt is neutralised to obtain valsartan then the said valsartan obtained remains contaminated with two nitrosamine impurities namely N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) is found to be 0.03 and 0.012 ppm respectively.

On the contrary as per the inventive and innovative finding of the inventors of the present invention, said two nitrosamine impurities namely N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) are not even detected confirming that the product obtained is free of nitrosoamine impurity or impurity if present is in undetectable level.

Particulars R&D Batches NDMA Impurity NDEA Impurity
Process comprising processing of unisolableand water soluble sodium salt of valsartan RD/VAL/2103/004 0.03 ppm 0.012 ppm
Process of the present invention comprising conversion of sodium salt of valsartan into isolable and water insoluble calcium salt of valsartan: RD/VAL/2110/52A Not detected Not detected
RD/VAL/2110/52B Not detected Not detected
RD/VAL/2110/53A Not detected Not detected
RD/VAL/2110/53B Not detected Not detected

Representative Liquid chromatograph Mass spectra (LCMS) chromatographs for standard solution based on prior art process and of sample solution based on instant novel process are illustrated herein in drawings.

Drawing-1: Representative chromatogram of LCMS analysis of Standard solution of product based on prior art process.

Drawing-2 Representative chromatogram of LCMS analysis of sample solution of product based on instant subject matter invention.

Referring to scheme-9, the embodiments of this invention and its advantages are further illustrated by the following, non-limiting Examples:
(Compound-3): Conversion of 2-(4'-Bromomethylphenyl)benzonitrile (Bromo-OTBN) (compound-1) into (S)-Methyl 2-(((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)amino)-3-methylbutanoate hydrochloride (compound-3):
To the solution of bromo-OTBN (compound-1) (100 g), charged in chloroform (300 mL), charged water (500 mL), sodium carbonate (55 g) and followed by L-valine methyl ester hydrochloride (compound-2) (75 g). Heat the reaction mixture at reflux temperature and maintain. After completion of reaction, separate out organic layer. Aqueous layer extracted by chloroform (100 mL). Combined organic layers washed with water (100 mL). Distil off chloroform completely. To the residual mass was charged toluene (400 mL), then slowly acidify. The obtained solid was isolated at by filtration followed by toluene wash (100 mL) to get (S)-Methyl 2-(((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)amino)-3-methylbutanoate hydrochloride (compound-3) (120 g).

(Compound-5): Conversion of (S)-Methyl 2-(((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)amino)-3-methylbutanoate hydrochloride (compound-3) into N-[(2'-Cyano[1,1'-biphenyl]-4-yl)methyl]-N-(1-oxopentyl)-L-valine methyl ester (compound-5)
To a solution of compound-3 (100 g) in MDC (350 mL), charged sodium carbonate (38.5 g). To this was added valeryl chloride (40.2 g) at 0-5°Candmaintain the reaction mass. After completion of reaction, slowly added water (300 mL). Organic layer separates out and aqueous layer was extracted by MDC (100 mL). Combined organic layers was washed with dilute HCl solution (100 mL), followed by aqueous sodium bicarbonate (100 mL). Finally organic phase was distilled to get oily mass (compound-5) which is forwarded for next step.

(Compound-6): Conversion of N-[(2'-Cyano[1,1'-biphenyl]-4-yl)methyl]-N-(1-oxopentyl)-L-valine methyl ester (compound-5) into N-(1-Oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine Methyl Ester (compound 6)
i. A solution of sodium azide (45.2 g) in water (300 mL) was added slowly tri butyl tin chloride (226.8g) and reaction mixture stirred at 35-40°C. Tributyltin azide layer (organic) separates out and aqueous layer extracted by o-xylene (50 mL). Combined organic layers forwarded for further reaction.
ii. The oily mass (Compound-5) from previous step (obtained from compound-3 100 g batch size) was charged with tributyl tin azide layer. o-xylene was distilled under reduced pressure. To the residual mass was charged with o-xylene (300 mL) and reaction mass heated to 140-145°C and maintained for 24h. After completion reaction, cool the reaction mass to 20-25°C and forwarded to next step.

(Compound-7): Conversion of N-(1-Oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine Methyl Ester (compound-6) into Valsartan sodium salt (compound-7)
To the dilute sodium hydroxide solution (250 mL water and 137 g 48% CS lye) charge compound-6 reaction mass (previous step reaction mass such) at temperature 20-25°C followed by TBAB (2 g). Maintain the biphasic reaction mass at 20-25°C. After completion of reaction, charge water (400 mL), separate out aqueous layer, washed by o-xylene (200 mL) followed by MDC (200 mL) and the aqueous solution forwarded to calcium salt formation.

(Compund-8): Conversion Valsartan sodium salt (compound-7) into Valsartan calcium salt (compound-8)
To the Aqueous solution valsartan sodium salt was added aqueous solution of calcium chloride (175 g in 200 mL water). Maintain the mass for 3-4 h. The solid was filtered and washed with water to get valsartan calcium salt, which is forwarded to breaking without drying.

Valsartan: Conversion of Valsartan calcium salt (compound-8) into valsartan
To the suspension of valsartan calcium salt wet cake (VAL-08) was suspended in water (500 mL) and MDC (400 mL) was added hydrochloric acid to adjust pH 2.0. Organic layer was separated out and aqueous layer re-extracted by MDC (2 x 100 mL). Combined Organic phase containing product washed with water. Distil off solvent from organic layer. To the residual mass charged ethyl acetate (700 mL) and subjected for carbon treatment. Clear solution of valsartan in ethyl acetate after carbon treatment, was gradually cooled to 0-5 °C. Filter the obtained solid mass and wash with pre-chilled ethyl acetate. Dry the compound at 60-65°C to get valsartan with purity 99.8% and nitrosamine impurity was not detected.
Contacting herein means reacting, mixing, stirring and the likes.

The term contacted used and contacting herein means reacted, mixed, stirred, refluxed and the likes.

WE CLAIM:

1. A process for controlling nitrosamine impurities during preparation of a compound of
formula (I)
HN
Formula I
Wherein R is selected from group
Valsartan Losartan Irbesartan Olmesartan Candesartan
comprising:
a. contacting compound of Formula E
Formula E: Sartan sodium salt
wherein R is defined as above
with alkaline earth metal salt to obtain corresponding water insoluble alkaline earth
metal salt of sartan of formula F:
Formula F: Sartan alkaline earth metal salt
M: Alkaline earth metal
wherein R is defined as above
b. isolating alkaline earth metal salt of sartan obtained in step a;
c. contacting alkaline earth metal salt of sartan from step b) with an acid to obtain
corresponding sartan of formula I having free or up to pharmaceutically acceptable limit
of nitrosoamine impurity(ies).
2. A process for the preparation of valsartan of formula II free of or containing
pharmaceutically acceptable nitrosoamine impurity comprising:
Formula II
a. contacting sodium salt of valsartan :
Valsartan sodium salt
with solution of alkaline earth metal salt to obtain corresponding water insoluble
alkaline earth metal salt of valsartan;
Valsartan alkaline earth metal salt
M: Alkaline earth metal
b. contacting alkaline earth metal salt of valsartan obtained in step a) with an acid to
obtain Valsartan of formula II having free or up to pharmaceutically acceptable
limit of nitrosoamine impurity(ies).
3. The process according to claims 1 and 2 wherein the alkaline earth metal salt is selected
from the group comprising calcium, magnesium, barium.
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4. The process according to claims 3 wherein the alkaline earth metal salt used is calcium
chloride.
5. The process according to claim 1 wherein the acid is HCl.