EP2900662A1 - 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 medoxomilInfo
- Publication number
- EP2900662A1 EP2900662A1 EP13779507.6A EP13779507A EP2900662A1 EP 2900662 A1 EP2900662 A1 EP 2900662A1 EP 13779507 A EP13779507 A EP 13779507A EP 2900662 A1 EP2900662 A1 EP 2900662A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- azilsartan medoxomil
- solvate
- dimethyl acetamide
- potassium salt
- methyl
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
- QJFSABGVXDWMIW-UHFFFAOYSA-N azilsartan medoxomil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C=3NC(=O)ON=3)C(OCC)=NC2=CC=CC=1C(=O)OCC=1OC(=O)OC=1C QJFSABGVXDWMIW-UHFFFAOYSA-N 0.000 title claims abstract description 62
- 239000003861 C09CA09 - Azilsartan medoxomil Substances 0.000 title claims abstract description 61
- 229960001211 azilsartan medoxomil Drugs 0.000 title claims abstract description 61
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 16
- 239000012453 solvate Substances 0.000 claims abstract description 41
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229940113088 dimethylacetamide Drugs 0.000 claims abstract description 29
- 239000000203 mixture Substances 0.000 claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 19
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 18
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 5
- 239000011591 potassium Substances 0.000 claims abstract description 5
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims abstract 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims abstract 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 39
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 19
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 8
- 229940011051 isopropyl acetate Drugs 0.000 claims description 8
- 230000005855 radiation Effects 0.000 claims description 8
- 229910016523 CuKa Inorganic materials 0.000 claims description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 4
- OBETXYAYXDNJHR-SSDOTTSWSA-M (2r)-2-ethylhexanoate Chemical compound CCCC[C@@H](CC)C([O-])=O OBETXYAYXDNJHR-SSDOTTSWSA-M 0.000 claims description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 3
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 3
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 3
- 230000001747 exhibiting effect Effects 0.000 claims 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 238000000113 differential scanning calorimetry Methods 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- 239000005485 Azilsartan Substances 0.000 description 4
- 229960002731 azilsartan Drugs 0.000 description 4
- KGSXMPPBFPAXLY-UHFFFAOYSA-N azilsartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NOC(=O)N1 KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 description 4
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000004807 desolvation Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- SSUBAQORPAUJGD-UHFFFAOYSA-N 1-methylpyrrolidin-2-one;pyrrolidin-2-one Chemical compound O=C1CCCN1.CN1CCCC1=O SSUBAQORPAUJGD-UHFFFAOYSA-N 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- DHROYPWJDYETPL-UHFFFAOYSA-N CC(N)=O.CC(N)=O Chemical compound CC(N)=O.CC(N)=O DHROYPWJDYETPL-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Epidemiology (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZ2012-663A CZ305318B6 (cs) | 2012-09-26 | 2012-09-26 | Způsob přípravy vysoce čisté draselné soli azilsartanu medoxomilu |
| PCT/CZ2013/000114 WO2014048404A1 (en) | 2012-09-26 | 2013-09-25 | A method of preparing a highly pure potassium salt of azilsartan medoxomil |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2900662A1 true EP2900662A1 (en) | 2015-08-05 |
Family
ID=66624776
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP13779507.6A Withdrawn EP2900662A1 (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) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ2014702A3 (cs) * | 2014-10-15 | 2016-04-27 | Zentiva, K.S. | Způsob přípravy vysoce čistého azilsartanu |
| 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 |
| 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 |
| CN115894472B (zh) * | 2022-12-14 | 2025-08-19 | 仁合益康集团有限公司 | 一种高纯度阿齐沙坦酯钾盐的制备方法 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7157584B2 (en) | 2004-02-25 | 2007-01-02 | Takeda Pharmaceutical Company Limited | Benzimidazole derivative and use thereof |
| 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 |
| WO2013042067A1 (en) * | 2011-09-20 | 2013-03-28 | Ranbaxy Laboratories Limited | Process for the preparation of potassium salt of azilsartan medoxomil |
| CN104039779B (zh) * | 2012-01-14 | 2016-08-24 | 广东东阳光药业有限公司 | 阿齐沙坦酯钾的晶型及其制备方法及其用途 |
| 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 JP JP2015533448A patent/JP2015532267A/ja active Pending
- 2013-09-25 CN CN201380050044.9A patent/CN104662019A/zh active Pending
- 2013-09-25 UA UAA201503960A patent/UA113668C2/uk unknown
- 2013-09-25 MX MX2015003209A patent/MX2015003209A/es unknown
- 2013-09-25 EA EA201590657A patent/EA028171B1/ru not_active IP Right Cessation
- 2013-09-25 KR KR1020157007800A patent/KR20150060733A/ko not_active Withdrawn
- 2013-09-25 EP EP13779507.6A patent/EP2900662A1/en not_active Withdrawn
- 2013-09-25 HK HK15106026.8A patent/HK1205505A1/xx unknown
- 2013-09-25 BR BR112015006572A patent/BR112015006572A2/pt not_active IP Right Cessation
- 2013-09-25 WO PCT/CZ2013/000114 patent/WO2014048404A1/en active Application Filing
-
2015
- 2015-03-22 IL IL237884A patent/IL237884A0/en unknown
Non-Patent Citations (2)
| Title |
|---|
| None * |
| See also references of WO2014048404A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| UA113668C2 (uk) | 2017-02-27 |
| CN104662019A (zh) | 2015-05-27 |
| HK1205505A1 (en) | 2015-12-18 |
| CZ305318B6 (cs) | 2015-07-29 |
| JP2015532267A (ja) | 2015-11-09 |
| EA201590657A1 (ru) | 2015-08-31 |
| EA028171B1 (ru) | 2017-10-31 |
| KR20150060733A (ko) | 2015-06-03 |
| WO2014048404A1 (en) | 2014-04-03 |
| IL237884A0 (en) | 2015-05-31 |
| BR112015006572A2 (pt) | 2017-07-04 |
| CZ2012663A3 (cs) | 2014-04-02 |
| MX2015003209A (es) | 2015-07-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2958625A1 (en) | Crystal of pyrrole derivative and method for producing the same | |
| EP2900662A1 (en) | A method of preparing a highly pure potassium salt of azilsartan medoxomil | |
| US20210188813A1 (en) | Ezh2 inhibitor and pharmaceutically acceptable salts and polymorphic substances thereof, and application of ezh2 inhibitor | |
| KR101275092B1 (ko) | 아질사르탄의 개선된 제조방법 | |
| US20150183767A1 (en) | Novel polymorphs of azilsartan medoxomil | |
| US9695147B2 (en) | Process for the preparation of perampanel | |
| 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 | |
| CA3059394C (en) | Preparation of 2-([1,2,3]triazol-2-yl)-benzoic acid derivatives | |
| EP2872499A1 (en) | Process for the preparation of intermediates for the synthesis of dabigatran etexilate, and crystalline forms of said intermediates | |
| WO2013156005A1 (en) | Method of preparing potassium salt of azilsartan medoxomil of high purity | |
| 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 | |
| JP2017535533A (ja) | 高純度のアジルサルタンを調製するための方法 | |
| KR20120129317A (ko) | 헤테로고리 화합물의 제조방법 | |
| JP2014530248A (ja) | ボセンタンの酸付加塩 | |
| KR101009404B1 (ko) | (에스)-엔-(1-카르복시-2-메틸-프로-1-필)-엔-펜타노일-엔-[2'-(1에이취-테트라졸-5-일)비페닐-4-일-메틸]아민화합물의 고순도 제조방법 | |
| 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 | |
| KR20240038023A (ko) | 식 i의 화합물의 결정형 및 이의 제조와 응용 | |
| JP2018197206A (ja) | アジルサルタン合成中間体の製造方法 | |
| EP2870151A2 (en) | Novel polymorphs of azilsartan | |
| JP2009102249A (ja) | ジベンゾオキセピン化合物の結晶の製造方法 | |
| JP2010100562A (ja) | アムロジピン製造中間体の精製方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 20150307 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
| AX | Request for extension of the european patent |
Extension state: BA ME |
|
| 17Q | First examination report despatched |
Effective date: 20170301 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
| 18D | Application deemed to be withdrawn |
Effective date: 20180404 |