WO2014048404A1 - Procédé de préparation d'un sel de potassium d'azilsartan médoxomil hautement pur - Google Patents

Procédé de préparation d'un sel de potassium d'azilsartan médoxomil hautement pur Download PDF

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Publication number
WO2014048404A1
WO2014048404A1 PCT/CZ2013/000114 CZ2013000114W WO2014048404A1 WO 2014048404 A1 WO2014048404 A1 WO 2014048404A1 CZ 2013000114 W CZ2013000114 W CZ 2013000114W WO 2014048404 A1 WO2014048404 A1 WO 2014048404A1
Authority
WO
WIPO (PCT)
Prior art keywords
azilsartan medoxomil
solvate
dimethyl acetamide
potassium salt
methyl
Prior art date
Application number
PCT/CZ2013/000114
Other languages
English (en)
Inventor
Jan Stach
Radim Krulis
Josef Cerny
Ludek Ridvan
Ondrej Dammer
Lukas KREJCIK
Stanislav Radl
Original Assignee
Zentiva, K.S.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zentiva, K.S. filed Critical Zentiva, K.S.
Priority to EA201590657A priority Critical patent/EA028171B1/ru
Priority to JP2015533448A priority patent/JP2015532267A/ja
Priority to BR112015006572A priority patent/BR112015006572A2/pt
Priority to MX2015003209A priority patent/MX2015003209A/es
Priority to KR1020157007800A priority patent/KR20150060733A/ko
Priority to UAA201503960A priority patent/UA113668C2/uk
Priority to EP13779507.6A priority patent/EP2900662A1/fr
Priority to CN201380050044.9A priority patent/CN104662019A/zh
Publication of WO2014048404A1 publication Critical patent/WO2014048404A1/fr
Priority to IL237884A priority patent/IL237884A0/en
Priority to HK15106026.8A priority patent/HK1205505A1/xx

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a method of preparation of the potassium salt of (5 -methyl oxo-l,3-dioxol-4-yl)methyl ester of l-[[2'-(2,5-dihydro-5-oxo-l,2 5 4-oxadiazol-3-yl)[l,l'- biphenyl]-4-yl]methyl]-2-ethoxy-lH-benzimidazole-7-carboxylic acid of formula (T)
  • azilsartan medoxomil (I), the synthesis of which is described in EP 1 718 641, EP 2 119 715, is used in the treatment of hypertension.
  • Azilsartan medoxomil is a "prodrug" that is easily enzymatically transformed to azilsartan, which is a highly selective antagonist of angiotensin II ATI receptors.
  • azilsartan medoxomil is prepared by a reaction of the free azilsartan acid with medoxomil alcohol, which provides azilsartan medoxomil as a solvate with dimethyl acetamide. This is then transformed, by crystallization of the product from an acetone/water mixture, to desolvated azilsartan medoxomil, which is subsequently converted to the potassium salt (I). Disclosure of Invention
  • This invention provides a method of preparing the potassium salt of azilsartan medoxomil of formula
  • a solvent which is dimethyl acetamide or N-methyl pyrrolidone or their mixtures with other solvents, is prepared, the resulting solvate is optionally re-crystallized, and, in the next step, converted, without desolvating, into the potassium salt using a potassium source.
  • the potassium source is, e.g., the potassium salt of 2-ethylhexanoic acid, and the solvent used for the conversion to the potassium salt is, e.g., acetone.
  • Azilsartan medoxomil (II) obtained in accordance with the patent EP 2 119 715 exhibits a maximum purity of 98.0% as determined by HPLC. Its desolvation according to the patent from an acetone/water mixture does not virtually achieve any further purification of the substance, nor does re-crystallization from an acetone/water mixture. Then, such raw material is not suitable for pharmaceutical production.
  • EP2 1 19 715 Azilsartan medoxomil Crystallized from a 90 % 99.77 % 0.03 % 0.09 % solvate with dimethyl dimethyl
  • both the solvates can also be prepared from a non-solvated form of azilsartan medoxomil by crystallization from dimethyl acetamide/isopropyl acetate or N- methyl pyrrolidone/isopropyl acetate mixtures, while the structurally similar dimethyl formamide does not form a solvate under these conditions.
  • Solid forms of azilsartan medoxomil can be described with methods commonly used for characterization of the solid phase, such as X-ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC).
  • a solvate of azilsartan medoxomil with dimethyl acetamide (1 :1) exhibits the following main characteristic peaks in the X-ray Powder Diffraction measured, with the use of CuKa radiation: 11.0; 12.1 ; 17.2, 25.3 ⁇ 0.2° 2theta, and further the following other characteristic peaks: 11.8; 19.5; 22.2; 24.3 ⁇ 0.2° 2theta.
  • Table 2 XRPD - characteristic diffraction peaks corresponding to a solvate of azilsartan medoxomil with dimethyl acetamide.
  • a solvate of azilsartan medoxomil with dimethyl acetamide can be prepared by crystallization from dimethyl acetamide and another solvent in which azilsartan medoxomil only dissolves to a limited extent, such as isopropyl acetate, isobutyl acetate, ethyl acetate, methyl acetate, acetone, methyl ethyl ketone and methyl isobutyl ketone. Crystallization is carried out at a temperature in the range of from 10°C to 100°C.
  • the potassium salt of azilsartan medoxomil is characterized by the following main peaks, measured with the use of CuKa radiation: 6.15°, 13.96°, 18.72° and 21.37° 2 ⁇ ⁇ 0.2° 2 ⁇ .
  • the characteristic XRPD peaks are presented in Table 3.and an XRPD record in Fig. 1. This form is further characterized with a Differential Scanning Calorimetry (DSC) record, see Fig.2.
  • a solvate of azilsartan medoxomil with N-methyl pyrrolidone is characterized by the following main characteristic peaks in an X-ray Powder record, measured with the use of CuKa radiation: 10.9; 16.3; 17.2; 18.9; ⁇ 0.2° 2theta.
  • the characteristic XRPD peaks are presented in Table 4 and the XRPD record in Fig 5. This form is further characterized with a Differential Scanning Calorimetry (DSC) record, see Fig. 6.
  • DSC Differential Scanning Calorimetry
  • Table 4 XRPD - characteristic diffraction peaks corresponding to a solvate of azilsartan medoxomil with N-methyl pyrrolidone.
  • a solvate of azilsartan medoxomil with N-methyl pyrrolidone can be prepared by crystallization from N-methyl pyrrolidone and another solvent in which azilsartan only dissolves to a limited extent, such as isopropyl acetate, isobutyl acetate, ethyl acetate, methyl acetate, acetone, methyl ethyl ketone and methyl isobutyl ketone. Crystallization is carried out at a temperature in the range of from 10°C to 100°C.
  • Fig. 1 X PD record for the potassium salt of azilsartan medoxomil
  • Fig. 2 DSC record for the potassium salt of azilsartan medoxomil
  • Fig. 3 XRPD record for a solvate of azilsartan medoxomil with dimethyl acetamide
  • Fig. 4 DSC record for a solvate of azilsartan medoxomil with dimethyl acetamide
  • Fig. 5 XRPD record for a solvate of azilsartan medoxomil with N-methyl pyrrolidone
  • Fig. 6 DSC record for a solvate of azilsartan medoxomil with N-methyl pyrrolidone
  • Soller diaphragms 0.02 rad and an anti-dispersion diaphragm 1 ⁇ 4 were used.
  • Soller diaphragms 0.02 rad and an anti-dispersion diaphragm 5.0 mm were used.
  • the Differential Scanning Calorimetry (DSC) records were measured with a DSC Pyris 1 device made by Perkin Elmer.
  • the charge of the sample in a standard Al pot was between 3-4 mg and the heating-up rate was 10°C/min.
  • the temperature program used consists of 1 minute of stabilization at the temperature of 50°C and then of heating to 250°C at the heating-up rate of 10°C/min.
  • As the carrier gas 4.0 N 2 was used at the flow of 20 ml/min.
  • Example 4 Preparation of azilsartan medoxomil as a solvate with dimethyl acetamide Crude azilsartan medoxomil prepared in accordance with Example 2 was dissolved in a mixture of dimethyl acetamide (4 ml) with isopropyl acetate (6 ml) in a hot state; after cooling and aspiration, 3.6 g (90 %) of the product was obtained, HPLC purity 99.77 %.
  • Example 5 Preparation of azilsartan medoxomil as a solvate withN-methyl pyrrolidone Crude azilsartan medoxomil prepared in accordance with Example 2 was dissolved in a mixture of N-methyl pyrrolidone (4 ml) with isopropyl acetate (7 ml) in a hot state; after cooling and aspiration, 2.8 g (69 %) of the product was obtained, HPLC purity 99.84 %.
  • Example 6 Preparation of the potassium salt of azilsartan medoxomil
  • Example 8 Preparation of the ethyl ester of 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH-benzo[i/]-imidazole-7-carboxylic acid (V).
  • the starting amidoxime (IV) was suspended in diethyl carbonate (30 g) and sodium ethoxide (21 % in ethanol, 9 g) was added. The mixture was heated at 80°C for 2h, 20 ml of the solvent was removed by distillation, ethanol (20 ml), water (20 ml) and acetic acid (3 g) and more water (20 ml) were added. The suspension was stirred at 50°C for 1 h and cooled to 25°C. 8 g (76 %) of the product was obtained.
  • the starting ethyl ester of azilsartan (V, 250 g) was suspended in a solution of sodium hydroxide in water (56 g/800ml). The suspension was heated at 50°C for 4 h, after pH adjustment to 4-5, the product crystallized providing 232 g (98.5 %).

Abstract

L'invention porte sur un procédé de préparation du sel de potassium d'azilsartan médoxomil de formule I, suivant lequel un solvate d'azilsartan médoxomil de formule II, avec un solvant choisi dans le groupe constitué par le diméthylacétamide, la N-méthylpyrrolidone ou leurs mélanges avec d'autres solvants, est préparé, ou recristallisé à partir de diméthylacétamide, de N-méthylpyrrolidine ou leurs mélanges avec d'autres solvants et, dans l'étape suivante, converti en le sel de potassium à l'aide d'une source de potassium dans un solvant approprié.
PCT/CZ2013/000114 2012-09-26 2013-09-25 Procédé de préparation d'un sel de potassium d'azilsartan médoxomil hautement pur WO2014048404A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
EA201590657A EA028171B1 (ru) 2012-09-26 2013-09-25 Способ получения высокочистой калиевой соли азилсартана медоксомила
JP2015533448A JP2015532267A (ja) 2012-09-26 2013-09-25 高純度のアジルサルタンメドキソミルのカリウム塩の製造方法
BR112015006572A BR112015006572A2 (pt) 2012-09-26 2013-09-25 método de preparação do sal de potássio de azilsartan medoxomil, solvato, e, sal de potássio de azilsartan medoxomil
MX2015003209A MX2015003209A (es) 2012-09-26 2013-09-25 Un metodo para preparar una sal potasica sumamente pura de azilsartan medoxomilo.
KR1020157007800A KR20150060733A (ko) 2012-09-26 2013-09-25 아질사르탄 메독소밀의 고순도 칼륨염을 제조하는 방법
UAA201503960A UA113668C2 (uk) 2012-09-26 2013-09-25 Спосіб одержання високочистої калієвої солі азилсартану медоксомілу
EP13779507.6A EP2900662A1 (fr) 2012-09-26 2013-09-25 Procédé de préparation d'un sel de potassium d'azilsartan médoxomil hautement pur
CN201380050044.9A CN104662019A (zh) 2012-09-26 2013-09-25 制备阿齐沙坦奥美沙坦酯的高纯度钾盐的方法
IL237884A IL237884A0 (en) 2012-09-26 2015-03-22 A method for preparing the potassium salt of azilsartan medoxomil with a high degree of purity
HK15106026.8A HK1205505A1 (en) 2012-09-26 2015-06-24 A method of preparing a highly pure potassium salt of azilsartan medoxomil

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZPV2012-663 2012-09-26
CZ2012-663A CZ305318B6 (cs) 2012-09-26 2012-09-26 Způsob přípravy vysoce čisté draselné soli azilsartanu medoxomilu

Publications (1)

Publication Number Publication Date
WO2014048404A1 true WO2014048404A1 (fr) 2014-04-03

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Country Status (12)

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EP (1) EP2900662A1 (fr)
JP (1) JP2015532267A (fr)
KR (1) KR20150060733A (fr)
CN (1) CN104662019A (fr)
BR (1) BR112015006572A2 (fr)
CZ (1) CZ305318B6 (fr)
EA (1) EA028171B1 (fr)
HK (1) HK1205505A1 (fr)
IL (1) IL237884A0 (fr)
MX (1) MX2015003209A (fr)
UA (1) UA113668C2 (fr)
WO (1) WO2014048404A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016058563A1 (fr) * 2014-10-15 2016-04-21 Zentiva, K.S. Procédé de préparation d'azilsartan très pur
CN105753854A (zh) * 2014-12-16 2016-07-13 重庆朗天制药有限公司 一种阿齐沙坦酯钾盐的新制备方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109071519A (zh) * 2016-01-28 2018-12-21 株式会社德山 阿齐沙坦及其制造方法
CN108727356A (zh) * 2018-06-28 2018-11-02 江苏新瑞药业有限公司 一种奥美沙坦酯碱金属盐的合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050187269A1 (en) * 2004-02-25 2005-08-25 Takeda Pharmaceutical Company Limited Benzimidazole derivative and use thereof
WO2013042067A1 (fr) * 2011-09-20 2013-03-28 Ranbaxy Laboratories Limited Procédé de préparation d'un sel de potassium de l'azilsartan médoxomil
WO2013104342A1 (fr) * 2012-01-14 2013-07-18 Sunshine Lake Pharma Co., Ltd. Formes cristallines de l'azilsartan médoxomil potassique et préparation et utilisations de celles-ci

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012090043A1 (fr) * 2010-12-29 2012-07-05 Jubilant Life Sciences Limited Nouvelles formes à l'état solide d'azilsartan médoxomil et leur procédé de préparation
US9233955B2 (en) * 2011-02-08 2016-01-12 Jubilant Life Sciences, Ltd. Process for the preparation of azilsartan medoxomil
CZ2012274A3 (cs) * 2012-04-19 2013-10-30 Zentiva, K.S. Zpusob prípravy vysoce cisté draselné soli azilsartanu medoxomilu

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050187269A1 (en) * 2004-02-25 2005-08-25 Takeda Pharmaceutical Company Limited Benzimidazole derivative and use thereof
EP1718641A2 (fr) 2004-02-25 2006-11-08 Takeda Pharmaceutical Company Limited Derives de benzimidazole et leur utilisation comme antagonistes du recepteur aii
EP2119715A1 (fr) 2004-02-25 2009-11-18 Takeda Pharmaceutical Company Limited Dérivé de benzimidazole et son utilisation en tant qu'antagoniste de récepteur
WO2013042067A1 (fr) * 2011-09-20 2013-03-28 Ranbaxy Laboratories Limited Procédé de préparation d'un sel de potassium de l'azilsartan médoxomil
WO2013104342A1 (fr) * 2012-01-14 2013-07-18 Sunshine Lake Pharma Co., Ltd. Formes cristallines de l'azilsartan médoxomil potassique et préparation et utilisations de celles-ci

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016058563A1 (fr) * 2014-10-15 2016-04-21 Zentiva, K.S. Procédé de préparation d'azilsartan très pur
CN105753854A (zh) * 2014-12-16 2016-07-13 重庆朗天制药有限公司 一种阿齐沙坦酯钾盐的新制备方法

Also Published As

Publication number Publication date
KR20150060733A (ko) 2015-06-03
MX2015003209A (es) 2015-07-14
CN104662019A (zh) 2015-05-27
HK1205505A1 (en) 2015-12-18
CZ2012663A3 (cs) 2014-04-02
IL237884A0 (en) 2015-05-31
BR112015006572A2 (pt) 2017-07-04
JP2015532267A (ja) 2015-11-09
EA028171B1 (ru) 2017-10-31
CZ305318B6 (cs) 2015-07-29
EP2900662A1 (fr) 2015-08-05
EA201590657A1 (ru) 2015-08-31
UA113668C2 (uk) 2017-02-27

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