CN105924400B - The preparation method of Azilsartan impurity A and B - Google Patents
The preparation method of Azilsartan impurity A and B Download PDFInfo
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- CN105924400B CN105924400B CN201610280740.4A CN201610280740A CN105924400B CN 105924400 B CN105924400 B CN 105924400B CN 201610280740 A CN201610280740 A CN 201610280740A CN 105924400 B CN105924400 B CN 105924400B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
Abstract
The present invention relates to a kind of preparation methods of Azilsartan impurity A and B, belong to the preparing technical field of Azilsartan impurity.The preparation method of Azilsartan impurity A of the present invention, Azilsartan intermediate II and carbonyl dimidazoles heating reflux reaction in organic solvent, impurity A is made, impurity A is heated in water with alkaline reagent and is reacted, impurity B is made, the chemical structural formula difference of Azilsartan intermediate II, impurity A and impurity B are as follows：
Description
Technical field
The present invention relates to a kind of preparation methods of Azilsartan impurity A and B, belong to the technology of preparing neck of Azilsartan impurity
Domain.
Background technology
Azilsartan (azilsartan, TAK-536) be the angiotensinⅡ of new generation developed of Japanese Wu Tian companies by
Body antagonist (ARB, husky smooth class), in January, 2012 is in Japan's approval listing.Azilsartan as Azilsartan prodrug,
Ratify to list in the U.S. within 2011, good therapeutic effect can be reached, it is also predicted pound drug Blopress that attaches most importance to
The subsequent product of (candesartan Cilexetil).
The preparation method and therapeutical uses of Azilsartan are in the existing announcements of patent EP0520423.Preparation method is as follows：
It is extremely important in terms of optimization and quality control since impurity of the drug is studied in pharmaceutical process, thus to Azilsartan
Miscellaneous Quality Research is also very necessary.But for Azilsartan major impurity A, ([[2'- (formamido) joins 2- ethyoxyls -1- at present
Benzene -4- bases] methyl] benzimidazole -7- carboxylate methyl esters) and impurity B (2- ethyoxyls -1- [[2'- (formamido) biphenyl -4- bases]
Methyl] benzimidazole -7- carboxylic acids) preparation be rarely reported.
Invention content
The purpose of the present invention is to provide a kind of preparation methods of Azilsartan impurity A and B, and simple for process, the period is short, system
Standby target product yield is high, is easy to purify.
The preparation method of Azilsartan impurity A of the present invention, Azilsartan intermediate II are having with carbonyl dimidazoles
The chemical structural formula difference of heating reflux reaction in solvent, obtained impurity A, Azilsartan intermediate II and impurity A is as follows：
After the completion of reaction, with the pH to 3~5 of hydrochloric acid conditioning solution, with a large amount of basic by-product miaows generated except dereaction
Azoles.
The molar ratio of the Azilsartan intermediate II and carbonyl dimidazoles is 1:1.05~1.1.Under the ratio, both
It can guarantee that intermediate II is reacted completely, while again being capable of control cost.
The organic solvent is 1,4- dioxane or tetrahydrofuran.
The reaction temperature can guarantee liquid reflux；The reaction time is 3-10h.
The method that Azilsartan impurity B is prepared using Azilsartan impurity A, be by impurity A and alkaline reagent in water
Heating reaction, is made impurity B, and the chemical structural formula of impurity B is as follows：
After the completion of reaction, with the pH to 2.3 ± 0.1 for the hydrochloric acid conditioning solution that molar concentration is 2M, for neutralizing unreacted
Alkali, while product is precipitated.
The alkaline reagent is lithium hydroxide, sodium hydroxide or potassium hydroxide.
Reaction temperature is 75 ± 3 DEG C, and the reaction time is 1-5 hours.
The present invention is by trans- 2- ethyoxyls -1- [[2 '-(2,5- dihydro -5- oxygen -1,2,4- oxadiazoles -3- bases) double benzene
Base -4- bases] methyl] benzimidazole -7- carboxylate methyl esters (intermediate II) are heated to reflux in a solvent with carbonyl dimidazoles (CDI),
Reaction to be completed in the case where being added without alkali, and major impurity A is prepared, impurity A hydrolyzes obtain impurity B under alkaline condition,
Equation is prepared to be exemplified below：
Traditional preparation method needs to be prepared using the chloro-carbonic acid ester type compound or other special agents of severe toxicity,
Technique toxicity is big, of high cost, and product is complicated, isolates and purifies difficulty.And the intermediate II used in the present invention is synthesis A Qisha
By-product during smooth can be used directly to prepare major impurity A and B, not need dedicated process equipment.The present invention selects
Property it is high, product is single, and the product of prospective quality is directly can be obtained using simple washing or recrystallization.
Compared with prior art, the present invention having the advantages that：
The synthesis of Azilsartan major impurity A and B explain impurity Producing reason, contribute to us in synthesis A Qisha
In smooth process, reaction route is designed, reaction condition is improved, reduces or avoid the formation of impurity, to preferably improve product
Quality.Present invention process is simple, and the period is short, and the target product yield of preparation is high, is easy to purify.
Specific implementation mode
With reference to embodiment, the present invention is further illustrated, but it is not intended to limit the implementation of the present invention.
Embodiment 1
10.0g (22.5mmol) intermediate II is added in 100 milliliters of Isosorbide-5-Nitrae-dioxane, is heated to flowing back, is slowly dripped
50 milliliters of Isosorbide-5-Nitrae-dioxane solutions for adding 3.84g (23.7mmol, 1.05eq) carbonyl dimidazoles, after being added dropwise to complete, reflux is anti-
It answers 5 hours；Stop reaction, vacuum distillation removes solvent；Ethyl acetate dissolves residue, and water, under stirring, HCl tune is added
PH to 3 is saved, stratification removes water phase；Water washing is added, liquid separation removes water phase, and organic phase saturated common salt water washing removes
Water phase, organic phase are cooled crystallization 1 hour with ice-water bath, and filtering, a small amount of ethyl acetate washing obtains impurity A, yield is
85%
Product has passed through the identification of mass spectrum and nuclear-magnetism：
ESI-MS：430.2 (M+1), 452.2 (M+Na).
1H-NMR(600MHz,DMSO-d6)δ:1.42 (3H, t, J=6Hz), 3.71 (3H, s), 4.62 (2H, q, J=6,
12Hz), 5.52 (2H, s), 6.96 (2H, d, J=6Hz), 7.20 (1H, t, J=6Hz), 7.25 (1H, s), 7.29-7.34 (3H,
M), 7.37-7.47 (4H, m), 7.62 (1H, s), 7.70 (1H, d, J=6Hz).
13C-NMR(150MHz,DMSO-d6)δ:14.5,46.4,52.4,66.8,115.7,121.0,123.0,126.1,
127.6,128.6,129.3,129.9,136.0,137.3,138.4,139.5,141.7,158.5,166.4,171.2。
Embodiment 2
10.0g (22.5mmol) intermediate II is added in 100 milliliters of tetrahydrofurans, is heated to flowing back, be slowly added dropwise
50 milliliters of tetrahydrofuran solutions of 4.01g (24.7mmol, 1.1eq) carbonyl dimidazoles, after being added dropwise to complete, back flow reaction 5 hours；
Stop reaction, vacuum distillation removes solvent；Ethyl acetate dissolves residue, and water is added, and under stirring, HCl adjusts pH to 5,
Stratification removes water phase；Water washing is added, liquid separation removes water phase, and organic phase saturated common salt water washing removes water phase, has
Machine is mutually cooled crystallization 1 hour with ice-water bath, filtering, and a small amount of ethyl acetate washing obtains impurity A.
Embodiment 3
4.3g impurity As are added in 100mL water, LiOH aqueous solutions to the solid that 2N is added dropwise dissolves, and adds 1mL, heats up
To 75 ± 3 DEG C, react 1 hour；
Stop heating, absolute ethyl alcohol is added, is cooled to 30 DEG C hereinafter, 2M-HCl adjusting pH to 2.3 ± 0.1, are slowly precipitated
White insoluble solids；Filtering purifies water washing, is washed with water three times, each 10mL, dry, obtains impurity B, is white powder
Shape solid, yield 99%.
Product has passed through the identification of mass spectrum and nuclear-magnetism：
ESI-MS：416.2 (M+1), 438.2 (M+Na).
1H-NMR(600MHz,DMSO-d6)δ:1.41 (3H, t, J=6,12Hz), 4.60 (2H, q, J=6,12,6Hz),
5.68 (2H, s), 7.04 (2H, q, J=6,12,12Hz), 7.18 (1H, t, J=6,12Hz), 7.26 (1H, s), 7.30-7.38
(4H, m), 7.41-7.47 (2H, m), 7.56 (1H, d, J=6Hz), 7.64 (1H, s), 7.68 (1H, d, J=6Hz), 13.13
(1H,br)。
13C-NMR(150MHz,DMSO-d6)δ:14.5,46.3,66.6,116.8,120.7,121.4,123.5,
126.3,127.0,127.5,128.6,129.2,129.9,131.2,136.4,137.3,138.3,139.4,141.7,
158.3,167.6,171.1。
Embodiment 4
4.3g impurity As are added in 100mL water, NaOH aqueous solutions to the solid that 2N is added dropwise dissolves, and adds 1mL, heats up
To 75 ± 3 DEG C, react 3 hours；
Stop heating, absolute ethyl alcohol is added, is cooled to 30 DEG C hereinafter, 2M-HCl adjustings pH=2.3 ± 0.1, is slowly precipitated
White insoluble solids；Filtering purifies water washing, is washed with water three times, each 10mL, dry, obtains impurity B.
Embodiment 5
4.3g impurity As are added in 100mL water, KOH aqueous solutions to the solid that 2N is added dropwise dissolves, and adds 1mL, is warming up to
It 75 ± 3 DEG C, reacts 5 hours；
Stop heating, absolute ethyl alcohol is added, is cooled to 30 DEG C hereinafter, 2M-HCl adjustings pH=2.3 ± 0.1, is slowly precipitated
White insoluble solids；Filtering purifies water washing, is washed with water three times, each 10mL, dry, obtains impurity B.
Claims (5)
1. a kind of preparation method of Azilsartan impurity A, it is characterised in that：Azilsartan intermediate II is having with carbonyl dimidazoles
It is heated to reflux in solvent, reaction is completed in the case where being added without alkali, impurity A, Azilsartan intermediate II and impurity A is made
Chemical structural formula difference it is as follows：
,。
2. the preparation method of Azilsartan impurity A according to claim 1, it is characterised in that：Azilsartan intermediate II
Molar ratio with carbonyl dimidazoles is 1:1.05 -1.1.
3. the preparation method of Azilsartan impurity A according to claim 1, it is characterised in that：Organic solvent is 1,4- bis-
Six ring of oxygen or tetrahydrofuran.
4. the preparation method of Azilsartan impurity A according to claim 1, it is characterised in that：Reaction time is 3-10h.
5. the preparation method of Azilsartan impurity A according to claim 1, it is characterised in that：After the completion of reaction, hydrochloric acid is used
Adjust the pH to 3- 5 of solution.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103664793A (en) * | 2012-09-24 | 2014-03-26 | 上海医药工业研究院 | Azilsartan intermediate and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103664793A (en) * | 2012-09-24 | 2014-03-26 | 上海医药工业研究院 | Azilsartan intermediate and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| Amildhydrationofnitrilescatalysedbycopper(II) acetate;Patricia Marcé，et al.;《Chem.Commun.》;20151120;第52卷;1436-1438 * |
| Microsomal Cytochrome P450 Dependent Oxidation of N-Hydroxyguanidines, Amidoximes, and Ketoximes: Mechanism of the Oxidative Cleavage of Their C=N(OH) Bond with Formation of Nitrogen Oxides;Anne Jousserandot，et al.;《Biochemistry》;19981118;第37卷(第49期);17179-17191 * |
| Related substances of azilsartan medoxomil: Synthesis and characterization;Madhuresh K. Sethi,et al.;《Der Pharma Chemica》;20151231;第7卷(第1期);20-28 * |
| Structural Elucidation of Potential Impurities in Azilsartan Bulk Drug by HPLC;Wentao Zhou，et al.;《Journal of AOAC International》;20141231;第97卷(第6期);1552-1562 * |
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