WO2023007502A1 - Procédé de préparation d'agents bloquants le récepteur de l'angiotensine ou leurs sels pharmaceutiquement acceptables - Google Patents

Procédé de préparation d'agents bloquants le récepteur de l'angiotensine ou leurs sels pharmaceutiquement acceptables Download PDF

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Publication number
WO2023007502A1
WO2023007502A1 PCT/IN2021/050829 IN2021050829W WO2023007502A1 WO 2023007502 A1 WO2023007502 A1 WO 2023007502A1 IN 2021050829 W IN2021050829 W IN 2021050829W WO 2023007502 A1 WO2023007502 A1 WO 2023007502A1
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WIPO (PCT)
Prior art keywords
biphenyl
azidomethyl
methyl
chloro
butyl
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PCT/IN2021/050829
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English (en)
Inventor
Saji Thomas
Rajendra SHEKHAWAT
M. Umamaheshwar PRASAD
Bidyut Biswas
Rohit Chakravarthy
Chetan Balubhai Patel
Anilkumar Haribhat Lingabhat
Mohan Chikmagalur SADASHIVAPPA
Indranil Nandi
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Jubilant Generics Limited
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Publication of WO2023007502A1 publication Critical patent/WO2023007502A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a process for the preparation of angiotensin receptor blockers or its pharmaceutically acceptable salts thereof. More particularly, the present invention relates to a simple, economical and industrially efficient process for the preparation of Losartan potassium of Formula I.
  • Losartan and its potassium salt are angiotensin-II receptor (Type ATI) antagonists.
  • Type ATI angiotensin-II receptor
  • U.S. Pat. No. 5,138,069 discloses and claims Losartan, its derivatives and pharmaceutically acceptable salts, including the potassium salt, as well as a method of treatment using pharmaceutically acceptable salts of Losartan.
  • This patent also discloses a process for the preparation of Losartan and its derivatives, which comprises de-protecting trityl-Losartan with hydrochloric acid to form free base of Losartan, and then adding aqueous potassium hydroxide-isopropanol solution to convert the free base to its potassium salt.
  • the known processes suffer from problems of purity of Losartan or its pharmaceutically acceptable salts thereof regarding presence of undesirable carcinogenic azido impurities.
  • the processes disclosed in the prior art fail to provide the control of carcinogenic/genotoxic azido impurities.
  • Azido impurities such as 5-(4'-(azidomethyl)-[l,l'-biphenyl]-2-yl)-lH-tetrazole, 4'- (azidomethyl)-[l,r-biphenyl]-2-carbonitrile, 4'-((5-(azidomethyl)-2-butyl-4-chloro-lH- imidazol- 1 -yl)methyl)-[ 1 , 1 '-biphenyl] -2-carbonitrile, 5 -(4'-((5 -(azidomethyl)-2-butyl-4- chloro- lH-imidazol- l-yl)methyl)-[ 1 , 1 '-biphenyl] -2 -yl)- lH-tetrazole, 5-(azidomethyl)-2- butyl-4-chloro-lH-imidazole, 4'-((4-(
  • the problem has been solved by providing an improved process, wherein Losartan or its pharmaceutically acceptable salts thereof is heated in presence of solvent with aqueous alkali to isolate pure Losartan or its pharmaceutically acceptable salts thereof, which is free from carcinogenic/genotoxic azido impurities and its carcinogenic precursor impurities.
  • the present invention relates to a process for the preparation of angiotensin receptor blockers namely Losartan, Valsartan, Candesartan, Olmesartan or Irbesartan or its pharmaceutically acceptable salts thereof containing less than 10 ppm of the azido impurities.
  • azido impurity is selected from the group comprising of 5-(4'-(azidomethyl)-[l,l'-biphenyl]-2-yl)-lH-tetrazole, 4'- (azidomethyl)-[l,r-biphenyl]-2-carbonitrile, 4'-((5-(azidomethyl)-2-butyl-4-chloro-lH- imidazol- 1 -yl)methyl)-[ 1 , 1 '-biphenyl] -2-carbonitrile, 5 -(4'-((5 -(azidomethyl)-2-butyl-4- chloro- lH-imidazol- l-yl)methyl)-[ 1 , 1 '-bi
  • the present invention relates to a process for the preparation of angiotensin receptor blockers namely Losartan, Valsartan, Candesartan, Olmesartan or Irbesartan or its pharmaceutically acceptable salts thereof containing less than 10 ppm of the azido impurities.
  • Losartan or its pharmaceutically acceptable salts thereof containing less than 10 ppm of each of the carcinogenic azido impurity is efficiently prepared by heating Losartan or its pharmaceutically acceptable salts thereof in solvent with aqueous alkali.
  • Heating Losartan or its pharmaceutically acceptable salts thereof, preferably potassium salt, in solvent with aqueous alkali helps in achieving Losartan or its pharmaceutically acceptable salts thereof containing less than 10 ppm of each of the carcinogenic azido impurity.
  • the present invention relates to a process for the preparation of angiotensin receptor blockers namely Losartan, Valsartan, Candesartan, Olmesartan or Irbesartan or its pharmaceutically acceptable salts thereof containing less than 10 ppm of the each of the azido impurities.
  • Azido impurities of Losartan or Losartan potassium are highly mutagenic/genotoxic/ carcinogenic and are point of concern during the synthesis of angiotensin receptor blockers. These azido impurities are:
  • the acceptable intake for each individual mutagenic impurity is less than 10 ppm.
  • the present invention relates to a process for the preparation of Losartan or its pharmaceutically acceptable salts thereof containing less than 10 ppm of each of the azido impurity, wherein azido impurity is selected from the group comprising of 5-(4'- (azidomethyl)-[ 1 , 1 '-biphenyl] -2-yl)- lH-tetrazole, 4'-(azidomethyl)- [ 1 , 1 '-biphenyl] -2- carbonitrile, 4'-((5-(azidomethyl)-2-butyl-4-chloro- lH-imidazol- 1 -yl)methyl)-[ 1 , 1 '- biphenyl] -2-carbonitrile, 5-(4'-((5-(azido methyl)-2-butyl-4-chloro-lH-imidazol-l- yl)methyl)-[ 1 , 1 '-
  • solvent is selected from the group comprising of water, organic solvent and mixture thereof.
  • Organic solvent is selected from the group comprising of hydrocarbon solvent, polar aprotic solvent, polar protic solvent, non-polar solvent and the like.
  • Organic solvent is further selected from the group comprising of pentane, hexane, 1,4-dioxane, diethyl ether, tetrahydrofuran (THF), ethyl acetate, toluene, xylene, acetone, dimethylformamide (DMF), acetonitrile (ACN), methanol, ethanol, propanol, n-butanol and the like.
  • alkali is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and magnesium hydroxide.
  • Alkali in step (i) is preferably sodium hydroxide or potassium hydroxide.
  • the concentration of aqueous sodium or potassium hydroxide solution is selected from 0.5% to 35%. Concentration of aqueous sodium or potassium hydroxide solution is preferably 2.5% to 5.0%.
  • step (i) mole equivalents of alkali w.r.t Losartan is from 0.1 to 5 mole equivalents.
  • potassium iodide, sodium iodide and the like can also be used along with aqueous sodium hydroxide solution for depletion of azido impurities.
  • reducing agents such as sodium borohydride, Lithium borohydride and the like can also be used along with aqueous base solution for depletion of the azido impurities.
  • step (ii) heating is carried out at temperature from 40°C to 110°C. Heating in step (ii) is carried out preferably at temperature from 90°C to 100°C. In step (ii), heating is carried out for 8 hours to 24 hours, preferably 10 hours to 15 hours.
  • isolation is performed by conventional means already known in prior art which includes but not limited to fdtration, distillation, crystallization, acid-base treatment and the like, preferably fdtration.
  • the Limit of Detection (LOD) for these azido impurities is 1 ppm.
  • the present invention relates to a process for the preparation of Losartan or its pharmaceutically acceptable salts thereof containing less than 10 ppm of each of the azido impurity, wherein azido impurity is selected from the group comprising of 5-(4'- (azidomethyl)- [ 1 , 1 '-biphenyl] -2-yl)- lH-tetrazole, 4'-(azidomethyl)- [ 1 , 1 '-biphenyl] -2- carbonitrile, 4'-((5-(azidomethyl)-2-butyl-4-chloro- lH-imidazol- 1 -yl)methyl)-[ 1 , 1 '- biphenyl] -2-carbonitrile, 5-(4'-((5-(azidomethyl)-2-butyl-4-chloro-lH-imidazol-l-yl) methyl)-[ 1 , 1 '-b
  • the present invention relates to process for the preparation of Losartan or its pharmaceutically acceptable salts thereof containing less than 10 ppm of each of the azido impurity, wherein azido impurity is selected from the group comprising of 5-(4'- (azidomethyl)- [ 1 , 1 '-biphenyl] -2-yl)- lH-tetrazole, 4'-(azidomethyl)- [ 1 , 1 '-biphenyl] -2- carbonitrile, 4'-((5-(azidomethyl)-2-butyl -4-chloro- lH-imidazol- 1 -yl)methyl)-[ 1 , 1 '- biphenyl] -2-carbonitrile, 5-(4'-((5-(azido methyl)-2-butyl-4-chloro-lH-imidazol-l- yl)methyl)-[ 1 , 1 '-b
  • step (ii) heating is carried out at temperature from 40°C to 110°C. Heating in step (ii) is carried out preferably at temperature from 90°C to 100°C.
  • step (ii) heating is carried out for 8 hours to 24 hours, preferably 10 hours to 15 hours.
  • the present invention relates to a process for the preparation of Losartan potassium containing less than 10 ppm of each of the azido impurity, wherein azido impurity is selected from the group comprising of 5-(4'-(azidomethyl)-[l,l'- biphenyl]-2-yl)-lH-tetrazole, 4'-(azidomethyl)-[l,r-biphenyl]-2-carbonitrile, 4'-((5- (azidomethyl)-2-butyl-4-chloro-lH-imidazol-l-yl)methyl)-[l,r-biphenyl]-2-carbonitrile, 5 -(4'-((5 -(azido methyl)-2 -butyl -4-chloro- lH-imidazol- 1 -yl)methyl)- [ 1 , 1 '-biphenyl] -2- yl)-
  • the present invention relates to a process for the preparation of Losartan or Losartan potassium containing less than 10 ppm of 5-(4'-((5-(azidomethyl)-2- butyl-4-chloro- lH-imidazol- 1 -yl)methyl)-[ 1 , l'-biphenyl] -2-yl)- lH-tetrazole of Formula V, comprising the steps of:
  • ICH M7 recommends that these mutagenic carcinogens be controlled at or below the acceptable cancer risk level. Due to their known potent carcinogenic effects, and because it is feasible to limit these impurities by taking reasonable steps to control or eliminate their presence, the goal is to have no quantifiable carcinogenic impurities or well within the declared limits which is safe for human consumption.
  • the present invention relates to a process for the preparation of Losartan potassium containing less than 10 ppm of each of the azido impurity.
  • Table 1 Depletion of mutagenic azido impurity by dissolving Losartan potassium in water and washing with organic solvent
  • the present applicant has found that there was no depletion of azido impurity in Losartan when heated in aqueous potassium carbonate solution.
  • Table 5 Content of various azido impurities in Losartan potassium while heating with Potassium carbonate
  • the present applicant has found that there was no depletion of azido impurity in Losartan potassium when heated in aqueous potassium carbonate solution.
  • Table 6 Content of various azido impurities in Losartan and Losartan potassium by employing the process of the instant invention
  • the problem has been solved by providing an improved process in which Losartan or its pharmaceutically acceptable salts thereof in solvent with aqueous alkali is heated and Losartan or its pharmaceutically acceptable salts thereof containing less than 10 ppm of each of the azido impurity is isolated.
  • the analytical method used for the determination of Azido impurities in Losartan or pharmaceutically acceptable salts thereof is either LCMS/LCMS-MS method or HPLC method.
  • the analytical method used for the determination of Azido impurities during reaction monitoring is HPLC method.
  • Azido impurities in isolated Losartan or its pharmaceutically acceptable salts thereof is LCMS or LCMS-MS method.
  • analytical method for the determination of azido impurities in Losartan or its pharmaceutically acceptable salts thereof is LCMS or LCMS-MS method, wherein azido impurity is selected from the group comprising of 5-(4'-(azidomethyl)-[l,r-biphenyl]-2- yl)-lH-tetrazole, 4'-(azidomethyl)-[l,r-biphenyl]-2-carbonitrile, 4'-((5-(azidomethyl)-2- butyl-4-chloro- lH-imidazol- 1 -yl)methyl)- [ 1 , 1 '-biphenyl] -2-carbonitrile, 5 -(4'-((5 -
  • LCMS-MS method Azido impurities in Losartan or Losartan potassium was determined by LCMS-MS method using ESI mode with mobile phase.
  • Mobile phase water/methanol: 720 mL/1280 mL methanol and 0.1% formic acid Using Column: Xbridge C8 150 x 4.6, 5m, Flow rate 0.8 mU/min
  • HPLC method Azido impurities in Losartan or Losartan potassium was determined by HPLC method with mobile phase lOmM phosphate buffer and 0.1% OPA, column Xterra RP 18, 250 x 4.5, 5 m column temperature 40°C, isocratic method with buffer and methanol.
  • Example-1 Preparation of ( l-((2 -( 1 //-Tetrazol-5-yl)( 1.1 -biphenyl )4-yl)methyl)-2- butyl-4-chloro- l//-imidazol-5 -yl)methanol
  • Tetrazole ring formation of 4’- ⁇ [2-Butyl-4-chloro-5-(hydroxymethyl)-lH-imidazole-l-yl] methyl ⁇ biphenyl-2-carbonitrile (100g) was performed using sodium azide (2.98 mole equivalent), triethylamine hydrochloride (3.30 mole equivalent), triethylamine (1.08 mole equivalent) and methyl isobutyl ketone (1.5V) as solvent. Reaction mass was heated at 95°C- 110°C and maintained for 30 hr-35 hr. After reaction, the organic layer was extracted with aqueous Potassium hydroxide solution.
  • Losartan was further purified by heating in 3.9% KOH solution (5 V) at 95°C-100°C for 12 hr-14 hr followed by isolation by adjusting the pH to 3.8-4.2 with the addition of dilute HC1 in presence of ethyl acetate and stirred for 6 hr-7 hr at 0°C-5°C. Filtered and isolated the product and dried it.
  • Example-2 Preparation of ( l-((2 -( 1 //-Tetrazol-5-yl)( 1.1 -biphenyl )4-yl)methyl)-2- butyl-4-chloro- l//-imidazol-5 -yljmethanol
  • Tetrazole ring formation of 4’- ⁇ [2-Butyl-4-chloro-5-(hydroxymethyl)-lH-imidazole-l-yl] methyl ⁇ biphenyl-2-carbonitrile (lOOg) was performed using sodium azide (2.98 mole equivalent), triethylamine hydrochloride (3.30 mole equivalent), tetrabutyl ammonium bromide and methyl isobutyl ketone (5 V) as solvent and reaction mass was heated at 95 °C -110°C and maintained for 30 hr - 35 hr.
  • the product was extracted into aqueous layer using 10% aqueous sodium hydroxide solution and this aqueous solution was heated to 12 hr - 24 hr at 95°C-100°C till the azido impurities weare below 10 ppm.
  • Losartan was isolated after pH is adjusted to 3.8-4.2 with addition of dilute HC1 in presence of ethyl acetate and stirred for 6 hr-7 hr at 0-5°C. Filtered and isolated the product. Dried the product initially at 25°C-30°C for 2 hr under vacuum and then at 60°C- 65 °C for 8 hr under vacuum.
  • Azido impurity 8ppm obtained from 5000-10000 ppm formed during tetrazole reaction
  • Example-3 Preparation of Potassium 5-
  • Example-4 Charged 3.9% KOH solution (19.5g KOH dissolved in DM water (500mL). Charged Losartan potassium (lOOg). Heated to 95°C-100°C and stirred for 12 hr - 20 hr. Cooled reaction mixture to 10°C-15°C. Charged ethyl acetate (300 mL) at 10°C-15°C. Slowly adjusted the pH to 3.8-4.2 with dilute HC1. Raised temperature of reaction mass to 25°C-30°C. Resulting mixture was stirred for 6 hr - 7 hr at 25°C-30°C. Cooled the reaction mass to 0°C-5°C and stirred for 2 hr at 0-5°C.
  • Azido impurity ⁇ lppm obtained from 200-500ppm Losartan Potassium.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne un procédé de préparation d'agents bloquants le récepteur de l'angiotensine ou de ses sels pharmaceutiquement acceptables contenant moins de 10 ppm d'impuretés azido. Plus particulièrement, la présente invention concerne un procédé de préparation de Losartan, de potassium de Losartan de formule I ou de ses autres sels pharmaceutiquement acceptables contenant moins de 10 ppm de chacune des impuretés azido, l'impureté azido étant choisie dans le groupe comprenant 5-(4'-(azidométhyl)-[1,1'-biphényl]-2-yl)-1H-tétrazole, 4'-(azidométhyl)-[1,1'-biphényl]-2-carbonitrile, 4'-((5-(azidométhyl)-2-butyl-4-chloro-1H-imidazol-1-yl)méthyl)-[1,1'-biphényl]-2-carbonitrile, 5-(4'-((5-(azidométhyl)-2-butyl-4-chloro-1H-imidazol-1-yl)méthyl)-[1,1'-biphényl]-2-yl)-1H-tétrazole, 5-(azidométhyl)-2-butyl-4-chloro-1H-imidazole, 4'-((4-(azidométhyl)-2-5 butyl-5-chloro-1H-imidazol-1-yl)méthyl)-[1,1'-biphényl]-2-carbonitrile, 5-(4'-((4-(azidométhyl)-2-butyl-5-chloro-1H-imidazol-1-yl)méthyl)-[1,1'-biphényl]-2-yl)-1H-tétrazole et 1-((1-((2'-(1H-tétrazol-5-yl)-[1,1'-biphényl]-4-yl)méthyl)-2-butyl-4-chloro-1H-imidazol-5-yl)méthyl)-5-(4'-((5-(azidométhyl)-2-butyl-4-chloro-1H-imidazol-1-yl)méthyl)-[1,1'-biphényl]-2-yl)-1H-tétrazole. Plus particulièrement, la présente invention concerne un procédé simple, économique et industriellement efficace pour la préparation de Losartan potassique de formule I.
PCT/IN2021/050829 2021-07-29 2021-08-27 Procédé de préparation d'agents bloquants le récepteur de l'angiotensine ou leurs sels pharmaceutiquement acceptables WO2023007502A1 (fr)

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WO2023046836A1 (fr) 2021-09-24 2023-03-30 Krka, D.D., Novo Mesto Procédé de préparation de sartans

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Publication number Priority date Publication date Assignee Title
WO2010029457A2 (fr) * 2008-09-09 2010-03-18 Alembic Limited Procédé de préparation amélioré du losartan potassique

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010029457A2 (fr) * 2008-09-09 2010-03-18 Alembic Limited Procédé de préparation amélioré du losartan potassique

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