CN104803998B - A kind of method for reducing impurity content - Google Patents
A kind of method for reducing impurity content Download PDFInfo
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- CN104803998B CN104803998B CN201510134875.5A CN201510134875A CN104803998B CN 104803998 B CN104803998 B CN 104803998B CN 201510134875 A CN201510134875 A CN 201510134875A CN 104803998 B CN104803998 B CN 104803998B
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- azilsartan
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- tetramer
- alkali
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- 239000012535 impurity Substances 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title abstract description 9
- 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 claims abstract description 61
- 239000005485 Azilsartan Substances 0.000 claims abstract description 52
- 229960002731 azilsartan Drugs 0.000 claims abstract description 51
- 239000003513 alkali Substances 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 239000002585 base Substances 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 3
- 150000002576 ketones Chemical class 0.000 abstract 2
- ABADUMLIAZCWJD-UHFFFAOYSA-N 1,3-dioxole Chemical compound C1OC=CO1 ABADUMLIAZCWJD-UHFFFAOYSA-N 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- URQLDGMCPXBYQF-UHFFFAOYSA-N C(O)C1=C(C=C(C(=O)O)C=C1C)C(=O)O Chemical class C(O)C1=C(C=C(C(=O)O)C=C1C)C(=O)O URQLDGMCPXBYQF-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 2
- 229940125364 angiotensin receptor blocker Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- PCJFEVUKVKQSSL-UHFFFAOYSA-N 2h-1,2,4-oxadiazol-5-one Chemical compound O=C1N=CNO1 PCJFEVUKVKQSSL-UHFFFAOYSA-N 0.000 description 1
- HXXOPVULXOEHTK-UHFFFAOYSA-N 4-methyl-1,3-dioxol-2-one Chemical compound CC1=COC(=O)O1 HXXOPVULXOEHTK-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical class N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 0 C*(C(c1ccccc1-c1ccc(C*(C(*)=*2)c3c2cccc3C(OC)=O)cc1)=*O1)C1=O Chemical compound C*(C(c1ccccc1-c1ccc(C*(C(*)=*2)c3c2cccc3C(OC)=O)cc1)=*O1)C1=O 0.000 description 1
- PZZSUSOQPCMUND-UHFFFAOYSA-N CC(O1)=C(COC)OC1=O Chemical compound CC(O1)=C(COC)OC1=O PZZSUSOQPCMUND-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 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
- 239000005480 Olmesartan Substances 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004105 azilsartan derivatives Chemical class 0.000 description 1
- 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 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 208000017574 dry cough Diseases 0.000 description 1
- 229940007183 edarbi Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 1
- 229960005117 olmesartan Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 229940093956 potassium carbonate Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 208000019553 vascular disease Diseases 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
-
- 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
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
The present invention relates to a kind of method for reducing impurity content, and in particular to a kind of preparation method of the low Azilsartan of content of Azilsartan tetramer impurity (4),It includes：Azilsartan (2) and the ketone (3) of 4 methylol, 5 methyl, 1,3 dioxole 2
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to a kind of reduction prepares Angiotensin Ⅱ receptor antagonist
(ARBs) method of the impurity produced during.
Background technology
Azilsartan, also referred to as (5- methyl -2- oxo -1,3- dioxole -4- bases) methyl 2- ethyoxyls -
1- { [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole -7- carboxylic acids
Ester, the Angiotensin Ⅱ receptor antagonist researched and developed by Japanese Takeda Pharmaceutical Company Limited (ARBs), is Azilsartan
(azilsartan) prodrug, for treating hypertension, shown in structure such as formula (I)：
On 2 25th, 2011, the sylvite (trade name Edarbi) of U.S. FDA approval Azilsartan was used to treat adult's height
Blood pressure, clinical research confirmation its there is steady lasting antihypertensive function.Clinical data is shown, with FDA approveds
Other two kinds selective angiotensin-ii receptor inhibitor Valsartans are compared with Olmesartan, and the medicine is reducing by 24 hours blood pressures
Aspect effect is more notable, also with steady decompression, will not cause the advantage of dry cough, while being also possible to reduce the heart by number of mechanisms
The risk of vascular diseases and diabetes.
The synthetic method for the Azilsartan (1) reported at present is to be condensed to make by Azilsartan (2) and side chain (3)
, such as PCT application WO2013156005 embodiments 1 method, paratoluensulfonyl chloride, DMAP, potassium carbonate, Azilsartan (2) and
Side chain (3) is added in dimethyl acetamide, after being reacted 3 hours under 8-10 degrees Celsius, post-processes to obtain Azilsartan, yield
80.1%, HPLC purity 97.6%,
Azilsartan its HPLC purity only 97.6% or so is prepared using this method, wherein there is a kind of content (HPLC of impurity
Peak area) more than 1.0%, generally 3.0% or so, Chinese patent application disclose CN 201410529424.7 report it is this
Impurity is that four molecule Azilsartans slough four molecules
The impurity (hereinafter referred to as Azilsartan tetramer impurity) formed after water, shown in its structure such as formula (4)：
This Azilsartan tetramer impurity (4) content is higher, is subsequently difficult to remove, and makes API be difficult to meet ICH Q7 rule
Fixed standard.During pharmaceutical synthesis, impurity is typically reduced by recrystallization repeatedly, the purity of product is improved, but instead
Multiple recrystallization is easily caused product loss, and yield declines.
The content of the invention
It is an object of the present invention to provide a kind of yield height and Azilsartan tetramer impurity, its structure such as formula (4) institute
Show, the preparation method of the low Azilsartan of content
In order to reach the purpose of the present invention, the present invention provides following technical scheme：
A kind of preparation method of the low Azilsartan of the content of Azilsartan tetramer impurity (4),
It includes：Azilsartan (2) and 4- methylol -5- methyl-1,3-dioxy heterocyclic pentene -2- ketone (3)
React in the presence of base, it is characterised in that the consumption of the alkali is more than 2.5 equivalents relative to Azilsartan (2).
Preferably, the consumption of described alkali is about 2.5 equivalents to about 4.0 equivalents relative to Azilsartan (2).
Preferably, described alkali is inorganic base such as potassium carbonate, sodium carbonate etc., or organic base such as triethylamine, ethylenediamine, N,
N- diisopropylethylamine etc., preferred described alkali is potassium carbonate, sodium carbonate, triethylamine, ethylenediamine or N, N- diisopropyl
Ethamine.
Preferably, described reaction is carried out under about -10 degrees Celsius to about 10 degrees Celsius, or carried out in ice bath.
Preferably, the preparation method of the low Azilsartan of the content of the Azilsartan tetramer impurity (4), it is wrapped
Include：Azilsartan (8.59g, 18.84mmol), DMAc (80ml), DMAP are sequentially added to the reaction vessel being placed in ice bath
After (0.5g), TsCl (3.9g), 4- methylol -5- methyl isophthalic acids, 3- dioxole -2- ketone (2.4g) stirring and dissolving, add
Alkali (57.1mmol), completion of dropping, mixture is warming up to 10 DEG C, and insulated and stirred 3 hours is added dropwise into reaction solution after completion of the reaction
0.3NHCl, adjusts pH to 5, and 60ml water is then slowly added dropwise, and separates out solid, and filtering is added into the solid of gained and is added dropwise
80ml acetone/waters (1：3) after, being stirred 2 hours at 35 DEG C, then stirring 3 hours, filtering in ice bath, 50 DEG C of vacuum drying 10h
Obtain Azilsartan.
Preferably, when the consumption of described alkali relative to Azilsartan (2) is about 2.5 equivalents to about 4.0 equivalents, this hair
The content HPLC (peak area) of the Azilsartan tetramer impurity (4) of the bright Azilsartan prepared is less than 0.1%, preferably
Less than 0.05%.
Another object of the present invention is to provide the method that a kind of " one kettle way " prepares Azilsartan (2), and it includes：At room temperature
(30 DEG C), into reaction bulb, addition compound 01 (180g, 1eq), toluene (540mL) and triethylamine (47.6g, 1.2eq) are obtained
Mixture, toluene (180mL) solution of ethyl chloroformate (51.1g, 1.2eq) is added drop-wise in above-mentioned reaction solution, after dripping off, and is continued
2h is stirred, after having reacted, reaction solution is cooled to room temperature, 600mL water is added, separates toluene layer, DMAP is added into toluene layer
(57.5g, 1.2eq), is warming up to backflow, stirs 3h, after having reacted, and reaction solution is cooled into room temperature, and 2mol/L hydroxides are added dropwise
Sodium water solution 1.2L stirring reaction 3h, 3.0 are adjusted to by reacting liquid pH value, insulated and stirred 1h, suction filtration, solid 200mL water wash,
Solid is dried in vacuo 12h at 50 DEG C and obtains Azilsartan (2)
In the context of the invention, "about" or "approximately" is exponential quantity within +/- 10% or within +/- 5%.
In the context of the invention, " room temperature " refers between 20 degrees Celsius to 35 degrees Celsius of temperature.
Beneficial effects of the present invention are as follows：
1. Azilsartan tetramer impurity (4) content produced during Azilsartan is prepared is high, be difficult to remove,
For this problem, we explore by continuous, it was found that in the case that the consumption of alkali in reaction is not enough, can produce a large amount of
Azilsartan tetramer impurity, but when alkali amount relative to Azilsartan (2) be 2.5 equivalents more than, the Azilsartan tetramer
Impurity content is to be reduced to less than 0.1%.
The method that " one kettle way " 2. provided by the present invention prepares Azilsartan, after reaction terminates, crude product high-efficient liquid phase color
HPLC purity is composed more than 99.0%, total recovery is more than 80%, using only a kind of solvent, beneficial to recovery, can industrialize amplification；
And without separation of intermediates in preparation process, it is easy to operate without post processing.
Embodiment
Embodiment described below specifically understands the present invention, is not that protection scope of the present invention is limited in following reality
Apply example.
Writing a Chinese character in simplified form in the context of the invention is expressed as follows：DMAc：DMA, DMAP:4- dimethylamino pyrroles
Pyridine, TsCl：Paratoluensulfonyl chloride, HPLC high performance liquid chromatography, h represents hour, and eq represents equivalent.
The preparation of the Azilsartan of embodiment 1
At room temperature (30 DEG C), compound 01 (180g, 1eq), toluene (540mL) and triethylamine are added into reaction bulb
(47.6g, 1.2eq) obtains mixture, and toluene (180mL) solution of ethyl chloroformate (51.1g, 1.2eq) is added drop-wise to above-mentioned anti-
Answer in liquid, after dripping off, continue to stir 2h, after having reacted, reaction solution is cooled to room temperature, 600mL water is added, separates toluene layer,
DMAP (57.5g, 1.2eq) is added into toluene layer, backflow is warming up to, 3h is stirred, after having reacted, reaction solution is cooled to room
Temperature, is added dropwise 2mol/L sodium hydrate aqueous solution 1.2L stirring reaction 3h, reacting liquid pH value is adjusted into 3.0, insulated and stirred 1h, taken out
Filter, solid 200mL water wash, solid is dried in vacuo 12h at 50 DEG C and obtains Azilsartan (2) total recovery about 89%.
Influence of the consumption of the alkali of embodiment 2 to Azilsartan tetramer impurity content
To the reaction vessel being placed in ice bath sequentially add Azilsartan (8.59g, 18.84mmol), DMAc (80ml),
After DMAP (0.5g), TsCl (3.9g), 4- methylol -5- methyl isophthalic acids, 3- dioxole -2- ketone (2.4g) stirring and dissolving,
The alkali added in table one, completion of dropping, mixture is warming up to 10 DEG C, insulated and stirred 3 hours, and reaction is finished.Dripped into reaction solution
Plus 0.3N HCl, pH to 5 is adjusted, 60ml water is then slowly added dropwise, solid is separated out, filtering adds drop into the solid of gained
Plus (V/V is 1 to 80ml acetone/waters：3) after, being stirred 2 hours at 35 DEG C, then stirring 3 hours, filtering, 50 DEG C of vacuum in ice bath
Dry 10h and obtain Azilsartan 7.8g, HPLC purity and Azilsartan tetramer impurity content such as institute of table one of Azilsartan
Show：
The influence of table one, the consumption of alkali to Azilsartan tetramer impurity content
The HPLC of the embodiment 2 of embodiment 3 testing conditions
Chromatographic column：Agilent Eclipse XDB C18 4.6*250mm, 5um
Mobile phase：A phases：10Mm ammonium acetates buffer salt (pH3.5) B phases：Acetonitrile
Detection wavelength：254nm flow velocitys：1.0ml/min column temperature：30℃
Run time：Run time after 60min：8min
Gradient：
| Time(min) | A% | B% |
| 0 | 55 | 45 |
| 8 | 55 | 45 |
| 18 | 40 | 60 |
| 28 | 10 | 90 |
| 60 | 10 | 90 |
Wherein, the retention time of Azilsartan tetramer impurity：38.36min, relative retention time 2.24.
Described above is only the better embodiment of the present invention, therefore all condition, features according to present patent application scope
And the equivalent change or modification that principle is done, it is included in the range of present patent application.
Claims (2)
1. a kind of preparation method of the low Azilsartan of Azilsartan tetramer impurity (4) content,
It includes：Azilsartan (2) and 4- methylol -5- methyl-1,3-dioxy heterocyclic pentene -2- ketone (3)
React in the presence of base, it is characterised in that the consumption of described alkali is 2.5 equivalents to 4.0 relative to Azilsartan (2)
Equivalent, described alkali is potassium carbonate, sodium carbonate, triethylamine, ethylenediamine or N, N- diisopropylethylamine, and described reaction is -10
Degree Celsius carried out under 10 degrees Celsius.
2. preparation method according to claim 1, it is characterised in that：The content of the Azilsartan tetramer impurity (4)
HPLC (peak area) is less than 0.1%.
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| CN115028589A (en) * | 2022-07-21 | 2022-09-09 | 浙江普洛家园药业有限公司 | Preparation method of azilsartan process impurity |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100503605C (en) * | 2004-02-25 | 2009-06-24 | 武田药品工业株式会社 | Benzimidazole derivative and its use as AII receptor antagonist |
| CN103664920A (en) * | 2012-09-24 | 2014-03-26 | 上海医药工业研究院 | Preparation method of azilsartan intermediate and azilsartan |
| WO2014049512A2 (en) * | 2012-09-26 | 2014-04-03 | Lupin Limited | Novel process for preparation of azilsartan medoxomil |
| CN104316608A (en) * | 2014-10-09 | 2015-01-28 | 广东东阳光药业有限公司 | Detection and preparation methods of azilsartan medoxomil impurities |
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| CN102766138B (en) * | 2012-07-23 | 2017-10-24 | 温州市人民医院 | A kind of preparation method of Azilsartan |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100503605C (en) * | 2004-02-25 | 2009-06-24 | 武田药品工业株式会社 | Benzimidazole derivative and its use as AII receptor antagonist |
| CN103664920A (en) * | 2012-09-24 | 2014-03-26 | 上海医药工业研究院 | Preparation method of azilsartan intermediate and azilsartan |
| WO2014049512A2 (en) * | 2012-09-26 | 2014-04-03 | Lupin Limited | Novel process for preparation of azilsartan medoxomil |
| CN104316608A (en) * | 2014-10-09 | 2015-01-28 | 广东东阳光药业有限公司 | Detection and preparation methods of azilsartan medoxomil impurities |
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