WO2023148748A1 - Procédé sûr amélioré pour la préparation de médicaments sartan de formule i - Google Patents

Procédé sûr amélioré pour la préparation de médicaments sartan de formule i Download PDF

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Publication number
WO2023148748A1
WO2023148748A1 PCT/IN2022/050434 IN2022050434W WO2023148748A1 WO 2023148748 A1 WO2023148748 A1 WO 2023148748A1 IN 2022050434 W IN2022050434 W IN 2022050434W WO 2023148748 A1 WO2023148748 A1 WO 2023148748A1
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Prior art keywords
valsartan
formula
earth metal
alkaline earth
sartan
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PCT/IN2022/050434
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English (en)
Inventor
Swapnil Sonar
Kamlesh Ranbhan
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Iol Chemicals And Pharmaceuticals Limited
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Publication of WO2023148748A1 publication Critical patent/WO2023148748A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Definitions

  • 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.
  • this invention discloses an improved safe process for the preparation of sartan drugs of Formula I
  • R is selected from group comprising:
  • nitrosamine This class of chemical compound comprises a nitrosyl group “-NO” connected to an amine.
  • 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.
  • a nitrosating agent such as nitrous acid, nitrosyl species, nitrogen oxides, and nitrite salts, etc.
  • Nitroso compounds of particular interest for the present invention are alkyl nitrosoamines which have been identified as carcinogens for a wide range of malian species. Nitrosoamines have been detected in many kinds of products such as pharmaceuticals, pesticides, cutting oils, cigarette smoke and foods like cheese, fish spices, etc.
  • nitrosamines are 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).
  • 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.
  • Valsartan is an Angiotensin II Receptor Blocker (ARB) and belongs to a family of analogue compounds commonly referred to as the sartans.
  • ARB Angiotensin II Receptor Blocker
  • 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).
  • NDMA N-nitrosodimethylamine
  • NDEA N-nitrosodiethylamine
  • NDIPA N- nitrosodiisopropylamine
  • NEIPA N -nitrosoethylisopropylamine
  • NMBA N nitroso-N- methyl-4-aminobutyric acid
  • 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
  • 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 azidejgets carried over into subsequent steps, despite purification operations, and these nitrites react with secondary or tertiary amines to generate nitrosamine impurities.
  • nitrite salts are present, carryover into subsequent steps cannot be ruled out.
  • 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):
  • 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.
  • Scheme-2 Route-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.
  • 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-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.
  • DMF tertiary amines or quaternary amines used therein are the potential amino substances in the process for the preparation of valsartan.
  • 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.
  • 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 LDso 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.
  • 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.
  • aqueous hydrochloric acid which results into generation of nitrous acid which forms nitrosamine impurity as disclosed herein before.
  • the reason for formation of unwanted nitrosamine impurity is the use of Aq. HC1 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.
  • 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.
  • 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.
  • ARBs angiotensin II receptor blocker
  • 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.
  • nitrosamines 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.
  • HNO2 nitrous acid
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 HC1 to give sartan drug molecule particularly valsartan free of nitrosoamine impurity.
  • an acid preferably HC1 to give sartan drug molecule particularly valsartan free of nitrosoamine impurity.
  • 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.
  • sartan of Formula I is prepared as per the SCHEME-10 as given herein below:
  • 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 HC1.
  • Valsartan is prepared as per the SCHEME- 11 as given herein below:
  • 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 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 HC1.
  • 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. HC1. 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.
  • Valsartan is prepared by the sequence disclosed in SCHEME-8.
  • 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.
  • 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.
  • NDMA N-nitrosodimethylamine
  • NDEA N- nitrosodiethylamine
  • Drawing-1 Representative chromatogram of LCMS analysis of Standard solution of product based on prior art process.
  • 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.
  • Valsartan Conversion of Valsartan calcium salt (compound-8) into valsartan
  • 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.
  • ethyl acetate 700 mL
  • ethyl acetate 700 mL
  • 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.
  • contacted used and contacting herein means reacted, mixed, stirred, refluxed and the likes.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé amélioré, sûr et nouveau pour l'élimination d'impuretés de nitrosamine pendant la préparation de la classe de sartan de médicaments contenant une structure cyclique de tétrazole représentée par la formule générale I, plus particulièrement une molécule de médicament de valsartan de formule II. En particulier, le procédé selon la présente invention comprend la conversion de sel de sodium soluble dans l'eau de valsartan en sel de métal alcalino-terreux insoluble dans l'eau de valsartan pour neutralisation avec de l'acide, ce qui permet d'éliminer la possibilité de transport d'agents de nitrosation responsables de la formation d'impuretés de nitrosamine.
PCT/IN2022/050434 2022-02-04 2022-05-06 Procédé sûr amélioré pour la préparation de médicaments sartan de formule i WO2023148748A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005049587A1 (fr) * 2003-11-21 2005-06-02 Ranbaxy Laboratories Limited Procede de preparation de tetrazole de biphenyle
WO2021022516A1 (fr) * 2019-08-07 2021-02-11 浙江华海药业股份有限公司 Procédé d'affinage de valsartan
CN112638885A (zh) * 2018-07-13 2021-04-09 浙江华海药业股份有限公司 一种缬沙坦的合成方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005049587A1 (fr) * 2003-11-21 2005-06-02 Ranbaxy Laboratories Limited Procede de preparation de tetrazole de biphenyle
CN112638885A (zh) * 2018-07-13 2021-04-09 浙江华海药业股份有限公司 一种缬沙坦的合成方法
WO2021022516A1 (fr) * 2019-08-07 2021-02-11 浙江华海药业股份有限公司 Procédé d'affinage de valsartan

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