WO2014048404A1 - A method of preparing a highly pure potassium salt of azilsartan medoxomil - Google Patents
A method of preparing a highly pure potassium salt of azilsartan medoxomil Download PDFInfo
- 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
Links
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 %).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Epidemiology (AREA)
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
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. |
EP13779507.6A EP2900662A1 (en) | 2012-09-26 | 2013-09-25 | A method of preparing a highly pure potassium salt of azilsartan medoxomil |
KR1020157007800A KR20150060733A (ko) | 2012-09-26 | 2013-09-25 | 아질사르탄 메독소밀의 고순도 칼륨염을 제조하는 방법 |
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 |
EA201590657A EA028171B1 (ru) | 2012-09-26 | 2013-09-25 | Способ получения высокочистой калиевой соли азилсартана медоксомила |
UAA201503960A UA113668C2 (uk) | 2012-09-26 | 2013-09-25 | Спосіб одержання високочистої калієвої солі азилсартану медоксомілу |
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 (en) | 2014-04-03 |
Family
ID=66624776
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CZ2013/000114 WO2014048404A1 (en) | 2012-09-26 | 2013-09-25 | A method of preparing a highly pure potassium salt of azilsartan medoxomil |
Country Status (12)
Country | Link |
---|---|
EP (1) | EP2900662A1 (cs) |
JP (1) | JP2015532267A (cs) |
KR (1) | KR20150060733A (cs) |
CN (1) | CN104662019A (cs) |
BR (1) | BR112015006572A2 (cs) |
CZ (1) | CZ305318B6 (cs) |
EA (1) | EA028171B1 (cs) |
HK (1) | HK1205505A1 (cs) |
IL (1) | IL237884A0 (cs) |
MX (1) | MX2015003209A (cs) |
UA (1) | UA113668C2 (cs) |
WO (1) | WO2014048404A1 (cs) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016058563A1 (en) * | 2014-10-15 | 2016-04-21 | Zentiva, K.S. | A process for preparing highly pure azilsartan |
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)
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)
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 (en) * | 2011-09-20 | 2013-03-28 | Ranbaxy Laboratories Limited | Process for the preparation of potassium salt of azilsartan medoxomil |
WO2013104342A1 (en) * | 2012-01-14 | 2013-07-18 | Sunshine Lake Pharma Co., Ltd. | Crystalline forms of azilsartan medoxomil potassium and preparation and uses thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012090043A1 (en) * | 2010-12-29 | 2012-07-05 | Jubilant Life Sciences Limited | Novel solid state forms of azilsartan medoxomil and preparation thereof |
JP2014505097A (ja) * | 2011-02-08 | 2014-02-27 | ジュビラント ライフ サイエンセズ リミテッド | アジルサルタンメドキソミルの改良製造方法 |
CZ2012274A3 (cs) * | 2012-04-19 | 2013-10-30 | Zentiva, K.S. | Zpusob prípravy vysoce cisté draselné soli azilsartanu medoxomilu |
-
2012
- 2012-09-26 CZ CZ2012-663A patent/CZ305318B6/cs not_active IP Right Cessation
-
2013
- 2013-09-25 CN CN201380050044.9A patent/CN104662019A/zh active Pending
- 2013-09-25 BR BR112015006572A patent/BR112015006572A2/pt not_active IP Right Cessation
- 2013-09-25 JP JP2015533448A patent/JP2015532267A/ja active Pending
- 2013-09-25 UA UAA201503960A patent/UA113668C2/uk unknown
- 2013-09-25 EP EP13779507.6A patent/EP2900662A1/en not_active Withdrawn
- 2013-09-25 KR KR1020157007800A patent/KR20150060733A/ko not_active Application Discontinuation
- 2013-09-25 WO PCT/CZ2013/000114 patent/WO2014048404A1/en active Application Filing
- 2013-09-25 EA EA201590657A patent/EA028171B1/ru not_active IP Right Cessation
- 2013-09-25 MX MX2015003209A patent/MX2015003209A/es unknown
-
2015
- 2015-03-22 IL IL237884A patent/IL237884A0/en unknown
- 2015-06-24 HK HK15106026.8A patent/HK1205505A1/xx unknown
Patent Citations (5)
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 (en) | 2004-02-25 | 2006-11-08 | Takeda Pharmaceutical Company Limited | Benzimidazole derivative and its use as aii receptor antagonist |
EP2119715A1 (en) | 2004-02-25 | 2009-11-18 | Takeda Pharmaceutical Company Limited | Benzimidazole derivative and its use as aii receptor antagonist |
WO2013042067A1 (en) * | 2011-09-20 | 2013-03-28 | Ranbaxy Laboratories Limited | Process for the preparation of potassium salt of azilsartan medoxomil |
WO2013104342A1 (en) * | 2012-01-14 | 2013-07-18 | Sunshine Lake Pharma Co., Ltd. | Crystalline forms of azilsartan medoxomil potassium and preparation and uses thereof |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016058563A1 (en) * | 2014-10-15 | 2016-04-21 | Zentiva, K.S. | A process for preparing highly pure azilsartan |
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 |
HK1205505A1 (en) | 2015-12-18 |
UA113668C2 (uk) | 2017-02-27 |
CZ305318B6 (cs) | 2015-07-29 |
IL237884A0 (en) | 2015-05-31 |
BR112015006572A2 (pt) | 2017-07-04 |
EP2900662A1 (en) | 2015-08-05 |
CZ2012663A3 (cs) | 2014-04-02 |
JP2015532267A (ja) | 2015-11-09 |
CN104662019A (zh) | 2015-05-27 |
EA201590657A1 (ru) | 2015-08-31 |
EA028171B1 (ru) | 2017-10-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2958625C (en) | Crystal of pyrrole derivative and method for producing the same | |
WO2014048404A1 (en) | A method of preparing a highly pure potassium salt of azilsartan medoxomil | |
US9624207B2 (en) | Polymorphs of azilsartan medoxomil | |
KR101275092B1 (ko) | 아질사르탄의 개선된 제조방법 | |
WO2018008219A1 (ja) | アジルサルタン中間体、アジルサルタン、及びこれらの製造方法 | |
EP2872499A1 (en) | Process for the preparation of intermediates for the synthesis of dabigatran etexilate, and crystalline forms of said intermediates | |
US9695147B2 (en) | Process for the preparation of perampanel | |
CA3059394C (en) | Preparation of 2-([1,2,3]triazol-2-yl)-benzoic acid derivatives | |
KR20200100615A (ko) | 3-(5-플루오로벤조푸란-3-일)-4-(5-메틸-5H-[1,3]디옥솔로[4,5-f]인돌-7-일)피롤-2,5-디온의 고체 형태 | |
WO2013156005A1 (en) | Method of preparing potassium salt of azilsartan medoxomil of high purity | |
KR20120129317A (ko) | 헤테로고리 화합물의 제조방법 | |
US20210188813A1 (en) | Ezh2 inhibitor and pharmaceutically acceptable salts and polymorphic substances thereof, and application of ezh2 inhibitor | |
JP2017535533A (ja) | 高純度のアジルサルタンを調製するための方法 | |
JP2014530248A (ja) | ボセンタンの酸付加塩 | |
JP2018076258A (ja) | アジルサルタンアルキルエステル、アジルサルタンメチルエステルの製造方法、及びアジルサルタンの製造方法 | |
JP2018197206A (ja) | アジルサルタン合成中間体の製造方法 | |
KR20240038023A (ko) | 식 i의 화합물의 결정형 및 이의 제조와 응용 | |
EP2870151A2 (en) | Novel polymorphs of azilsartan | |
JP2010100562A (ja) | アムロジピン製造中間体の精製方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 13779507 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2013779507 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2015/003209 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 237884 Country of ref document: IL |
|
ENP | Entry into the national phase |
Ref document number: 20157007800 Country of ref document: KR Kind code of ref document: A Ref document number: 2015533448 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112015006572 Country of ref document: BR |
|
WWE | Wipo information: entry into national phase |
Ref document number: A201503960 Country of ref document: UA Ref document number: 201590657 Country of ref document: EA |
|
ENP | Entry into the national phase |
Ref document number: 112015006572 Country of ref document: BR Kind code of ref document: A2 Effective date: 20150324 |