EP2838896A1 - Method of preparing potassium salt of azilsartan medoxomil of high purity - Google Patents
Method of preparing potassium salt of azilsartan medoxomil of high purityInfo
- Publication number
- EP2838896A1 EP2838896A1 EP13725551.9A EP13725551A EP2838896A1 EP 2838896 A1 EP2838896 A1 EP 2838896A1 EP 13725551 A EP13725551 A EP 13725551A EP 2838896 A1 EP2838896 A1 EP 2838896A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- azilsartan medoxomil
- solvate
- potassium salt
- tetrahydrofuran
- acetone
- 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- Withdrawn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
- 239000003861 C09CA09 - Azilsartan medoxomil Substances 0.000 title claims abstract description 84
- 229960001211 azilsartan medoxomil Drugs 0.000 title claims abstract description 84
- 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 84
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 50
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 41
- 239000012453 solvate Substances 0.000 claims description 38
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 32
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 8
- 238000009835 boiling Methods 0.000 claims description 7
- 229910016523 CuKa Inorganic materials 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 230000005855 radiation Effects 0.000 claims description 5
- OBETXYAYXDNJHR-SSDOTTSWSA-M (2r)-2-ethylhexanoate Chemical compound CCCC[C@@H](CC)C([O-])=O OBETXYAYXDNJHR-SSDOTTSWSA-M 0.000 claims description 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 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 abstract description 3
- -1 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl Chemical group 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- 238000001816 cooling Methods 0.000 description 15
- 238000000113 differential scanning calorimetry Methods 0.000 description 14
- 239000013078 crystal Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 5
- 238000004817 gas chromatography Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- ZUFQCVZBBNZMKD-UHFFFAOYSA-M potassium 2-ethylhexanoate Chemical compound [K+].CCCCC(CC)C([O-])=O ZUFQCVZBBNZMKD-UHFFFAOYSA-M 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 239000005485 Azilsartan Substances 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 229960002731 azilsartan Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000000543 intermediate Substances 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
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 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
- 238000003786 synthesis reaction Methods 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
Definitions
- Azilsartan medoxomil the synthesis of which is described in EP1718641 and EP21 19715, is used in treating high blood pressure.
- Azilsartan medoxomil is the so-called prodrug, which can be easily enzymatically transformed to azilsartan, a highly selective blocker of angiotensin II ATI receptors.
- the differential scanning calorimetry (DSC) measurements were performed using a Pyris 1 DSC calorimeter from Perkin Elmer. The weighed amount of the sample in a standard Al pan was 3 - 4 mg, heating rate 10°C/min. The temperature program included stabilization at 50°C for 1 minute and heating to 250°C at a heating rate of 10°C/min. The purge gas was 4.0 N 2 of flow rate 20 ml/min.
- Example 7 Preparation of the potassium salt of azilsartan medoxomil from the acetone solvate of azilsartan medoxomil
- the azilsartan medoxomil solvate (7 g) from Example 4 was dissolved in tetrahydrofuran (250 ml). After cooling to 0°C, a solution of 2-ethylhexanoic acid potassium salt (2.2 g) in tetrahydrofuran (20 ml) was added dropwise. After stirring at 0°C for 1 hour, the precipitated crystals were sucked off and dried. Yield: 5.3 g (78%). HPLC purity: 99.8%.
- Example 13 Preparation of non-solvated azilsartan medoxomil Crude azilsartan medoxomil (1 g) was hot-dissolved in methylacetate and, after cooling, 0.65 g (65%) of the product was obtained. HPLC purity: 98.1%.
- Example 14 Preparation of non-solvated azilsartan medoxomil
- Example 16 Preparation of non-solvated azilsartan medoxomil Crude azilsartan medoxomil (1 g) was dissolved in aqueous potassium carbonate (10 ml, 10%); acetone (10 ml) was added and the product was re-precipitated with acetic acid (3 ml). 0.74 g (74%) of the product was obtained. HPLC purity: 98.1 %.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZ20120274A CZ2012274A3 (cs) | 2012-04-19 | 2012-04-19 | Zpusob prípravy vysoce cisté draselné soli azilsartanu medoxomilu |
| PCT/CZ2013/000049 WO2013156005A1 (en) | 2012-04-19 | 2013-04-15 | Method of preparing potassium salt of azilsartan medoxomil of high purity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2838896A1 true EP2838896A1 (en) | 2015-02-25 |
Family
ID=48536652
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP13725551.9A Withdrawn EP2838896A1 (en) | 2012-04-19 | 2013-04-15 | Method of preparing potassium salt of azilsartan medoxomil of high purity |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP2838896A1 (cs) |
| CZ (1) | CZ2012274A3 (cs) |
| WO (1) | WO2013156005A1 (cs) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ305318B6 (cs) * | 2012-09-26 | 2015-07-29 | Zentiva, K.S. | Způsob přípravy vysoce čisté draselné soli azilsartanu medoxomilu |
| WO2017131218A1 (ja) * | 2016-01-28 | 2017-08-03 | 株式会社トクヤマ | アジルサルタン及びその製造方法 |
| CN116903606A (zh) * | 2023-07-19 | 2023-10-20 | 迪嘉药业集团股份有限公司 | 一种美阿沙坦钾杂质及其制备方法 |
| CN117126150A (zh) * | 2023-08-29 | 2023-11-28 | 仁合益康集团有限公司 | 一种阿齐沙坦酯钾盐杂质a的制备方法 |
Family Cites Families (3)
| 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 |
| WO2013042067A1 (en) * | 2011-09-20 | 2013-03-28 | Ranbaxy Laboratories Limited | Process for the preparation of potassium salt of azilsartan medoxomil |
-
2012
- 2012-04-19 CZ CZ20120274A patent/CZ2012274A3/cs unknown
-
2013
- 2013-04-15 WO PCT/CZ2013/000049 patent/WO2013156005A1/en active Application Filing
- 2013-04-15 EP EP13725551.9A patent/EP2838896A1/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2013156005A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2013156005A1 (en) | 2013-10-24 |
| CZ2012274A3 (cs) | 2013-10-30 |
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