CN105712984A - Preparation method of Azilsartan - Google Patents
Preparation method of Azilsartan Download PDFInfo
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- CN105712984A CN105712984A CN201610120276.2A CN201610120276A CN105712984A CN 105712984 A CN105712984 A CN 105712984A CN 201610120276 A CN201610120276 A CN 201610120276A CN 105712984 A CN105712984 A CN 105712984A
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- 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
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Abstract
The invention discloses a preparation method of Azilsartan. The method includes the specific steps of using 2-oxethyl-1-{[((2'-hydroxyl aminoimino)bis-phenyl)-4-base]-methyl}-1H-benzimidazole-7-carboxylic ethyl ester as the start raw material C6, conducting addition on the raw material and hydroxylamine hydrochloride to obtain Azilsartan oxime, synthesizing Azilsartan oxime and N,N'-carbonyldimidazole (CDI) to obtain Azilsartan ethyl ester, and finally conducting hydrolysis and purification to obtain Azilsartan. Compared with the traditional process using 2-ethoxyl-1-(2'-cyano-biphenyl-4-)base)methylbenzimidazole-7-methyl formate as the start raw material, the number of types of generated impurities is decreased, and the purification difficulty is lowered. The whole method is mild in reaction, no highly-toxic and high-boiling-point solvent is used, the product yield is high, purity can reach 99.9% or above, and the requirements for industrialized raw material agent production are met.
Description
Technical field
The present invention devises the preparation method of a kind of crude drug, is specifically related to the preparation method of Azilsartan, belongs to medicine
Synthesis field.
Background technology
Azilsartan is a kind of Angiotensin Ⅱ receptor antagonist medicine, is used for treating hypertension, is also the most only
One Angiotensin Ⅱ receptor antagonist (the husky smooth class) medicine being in late-stage clinical, has wide market prospect.By Japan
Takeda Pharmaceutical Company Limited develops, and in listing in 2012, Azilsartan was the prodrug of this medicine.
Azilsartan, English common name: Azilsartan
Chemical name: 2-ethyoxyl-1-[[2 '-(4,5-dihydro-5-oxo-1,2,4-diazole-3-base) biphenyl-4-base] methyl]
Benzimidazole-7-carboxylic acid
English name: 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-
4-yl]methyl] benzimidazole-7-carboxylic acid
No. CAS: 147403-03-0
Structural formula is as follows:
Molecular formula: C25H20N4O5
Molecular weight: 456.45
Polymorphism: this product exists polymorphic, the drug crystal forms produced for preparation is defined as A crystal formation.
United States Patent (USP) US5583141 discloses with 2-ethyoxyl-1-(2 '-cyanobiphenyl-4-base) tolimidazole-7-
Methyl formate is initiation material, reacts addition with oxammonium hydrochloride. and obtain hydroxyoxime under the conditions of Feldalat NM does alkali, then with chloro-carbonic acid
Ethyl ester carries out ring-closure reaction, obtains Azilsartan methyl ester structure, obtains Azilsartan finally by hydrolysis.What the method existed asks
Topic is that second step ring-closure reaction refluxes in dimethylbenzene, and temperature is high, and impurity is many, and yield is low, it is difficult to meet the market demand.
The Chinese patent of Application No. 201310744903.6 discloses a kind of route: Azilsartan nitrile and oxammonium hydrochloride.,
After obtaining hydroxyoxime in dimethyl sulfoxide, then dripping carbonyl pass cyclization reagent, finally hydrolysis obtains Azilsartan.Embodiment uses
Severe toxicity, the phosgene of highly corrosive, the carbonyl such as surpalite closes cyclization reagent, is unfavorable for amplifying and produces；If substituting by dimethyl carbonate etc.,
Activity is slightly worse, and yield reduces.
Another kind is that the Chinese patent of Application No. 201410437473.8 discloses another kind of route: be also with 2-ethoxy
Base-1-(2 '-cyanobiphenyl-4-base) tolimidazole-7-methyl formate is initiation material, in dioxane successively with salt
Acid azanol addition, CDI cyclization, treat different things alike and obtain Azilsartan methyl ester, then prepares Azilsartan through hydrolysis two-step reaction altogether.First
First, employing high boiling solvent dioxane in the method, when evaporated under reduced pressure dioxane, temperature is higher, and benzimidazole ring
On ethyoxyl unstable, de-ethyl impurity can be produced, structure is as follows:
During ethyl alcohol recrystallization, owing to recrystallization temperature is higher, following impurity also can be produced:
Add 3 intermediate:
Having 9 impurity, dopant species adds refined difficulty and step more, causes cost to raise.
Summary of the invention
For deficiency of the prior art, the invention discloses the preparation method that a kind of Azilsartan is new, this method synthesizes
Route is short, and impurity is few, can avoid the subtractive process of complexity, and Azilsartan purity is high, detects through HPLC, purity >=99.9%.
The method comprises the steps:
1) initiation material C6 is in second alcohol and water, under the effect of alkali, after oxammonium hydrochloride. additive reaction, is cooled to room temperature and takes out
Filter, after filter cake washing, pulls an oar with dilute hydrochloric acid, and the filtrate that sucking filtration obtains is extracted with ethyl acetate, and sodium hydroxide solution is used in water intaking mutually
Adjust pH to 9～11, after the filter cake dehydrated alcohol backflow making beating that sucking filtration obtains, 45～65 DEG C of vacuum drying after sucking filtration is the most dry,
To Azilsartan oxime；
2) the Azilsartan oxime prepared in step 1) and N, N '-carbonyl dimidazoles (CDI) cyclization in the basic conditions, reaction obtains
Azilsartan ethyl ester, uses NaHSO3Aqueous solution cancellation is reacted, ethyl acetate extractive reaction liquid, more organic with saturated aqueous common salt washing
Phase, evaporated under reduced pressure solvent, pull an oar with alcohol reflux, sucking filtration gained solid 35～45 DEG C of vacuum drying；
3) step 2) in the Azilsartan ethyl ester for preparing be hydrolyzed in sodium hydrate aqueous solution reaction, regulate pH with dilute hydrochloric acid
To 3.5～4.5, adding sucking filtration after acetone stirring, after filter cake alcohol flushing, it is thick that 35～45 DEG C of vacuum drying obtain Azilsartan
Product；
4) the refined crystalline substance that turns of the Azilsartan crude product dehydrated alcohol prepared in step 3) i.e. obtains Azilsartan, and 35～45 DEG C of vacuum are done
Dry.
Its course of reaction is shown below:
Purpose to better implement the present invention, disclosing the initiation material C6 described in step 1) is 2-ethyoxyl-1-
{ [((2 '-hydroxyl ammonia auxotox radical) double phenyl)-4-base]-methyl }-1H-benzimidazole--7-carboxylic acid, ethyl ester.
Further disclosing the alkali described in step 1) is triethylamine.
The temperature of the additive reaction further disclosing the initiation material C6 described in step 1) and oxammonium hydrochloride. be 82～
90 DEG C, the response time is 8～10h, preferably 10h.
The mol ratio further disclosing initiation material C6, oxammonium hydrochloride. and the triethylamine described in step 1) is 1: 5
～10: 5～10, preferably 1: 10: 10.
The mass concentration further disclosing the sodium hydroxide solution described in step 1) is 10～50%, preferably 30%.
Further disclose step 1) and step 2) described in dehydrated alcohol beating time 20min～40min, preferably
30min。
Further disclose step 2) described in alkali be 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU).
Further disclose step 2) described in Azilsartan oxime, the mol ratio of CDI and DBU be: 1: 1.2～1.8
: 1.2～1.8, preferably 1: 1.8: 1.8.
Further disclose step 2) described in ring-closure reaction temperature be 20～30 DEG C, preferably 25 DEG C；Response time is 1
～2h, preferably 90min.
Further disclose step 2) described in vacuum distillation temperature be 40～45 DEG C.
The mass concentration further disclosing the sodium hydrate aqueous solution described in step 3) is 5～10%, preferably 10%；Ah
The mol ratio of Qi Shatan ethyl ester and sodium hydroxide is 1: 3～10, preferably 1: 10.
Further disclosing the hydrolysis temperature described in step 3) is 50～70 DEG C, preferably 70 DEG C；Response time be 1～
2h, preferably 90min.
The mass concentration further disclosing the dilute hydrochloric acid described in step 3) is 10%, and regulation pH is 2.5～4.5, preferably
3.3。
Further disclosing the recrystallization temperature described in step 4) is 75～78 DEG C.
It is an advantage of the current invention that: selection 2-ethyoxyl-1-{ [((2 '-hydroxyl ammonia auxotox radical) double phenyl)-4-base]-
Methyl }-1H-benzimidazole--7-carboxylic acid, ethyl ester is initiation material, obtains Azilsartan through three-step reaction and an one-step refining, due to
Ethyoxyl on benzimidazole ring is unstable, can produce following impurity:
Plus 3 intermediate C6, C7 and C8, having 7 impurity, compared to traditional handicraft, with 2-ethyoxyl-1-, (2 '-cyano group joins
Benzene-4-base) tolimidazole-7-methyl formate is as initiation material, it is to avoid the generation of 2 kinds of impurity, reduce refined step
Rapid difficulty；Whole method reaction gentleness, does not uses severe toxicity, high boiling solvent, and product yield is high, and purity can reach 99.9%
Above, the demand of crude drug industrialized production is met.
Accompanying drawing illustrates: Fig. 1 is the HPLC spectrogram of Azilsartan in embodiment 1；
Fig. 2 is the HPLC spectrogram of Azilsartan in embodiment 2.
Present disclosure is described in further detail by form more by the following examples, but should not be interpreted as this with regard to this
It is only limitted to following example in inventing above-mentioned subject area.Without departing under the present invention above-mentioned technology premise, general according to this area
The corresponding amendment replaced or change that logical technological know-how and customary means are made, is included within the scope of the present invention.
Embodiment 1
The synthesis of 1.C7 compound
50L double-layer glass reaction kettle adds oxammonium hydrochloride. 7.3 kilograms (10eq) and 5.3 liters of water, stirs 10min, add three second
Amine 10.6 kilograms (10eq), stirs 10min.Add initiation material C6 4.5 kilograms (1eq), 26.5 liter of 95% ethanol, stir evenly.Throw
After having expected, starting to warm up to backflow, reflux 10h.TLC follows the tracks of reaction process, after raw material fundamental reaction completes, stops adding
Heat, is naturally cooling to 20～35 DEG C.Sucking filtration, filter cake is with 5 liters of washings.Filter cake is put in reactor, add dilute hydrochloric acid (2.6 liters
Concentrated hydrochloric acid is made into 26 aqueous solution), pull an oar 90min.Sucking filtration, filtrate extracts by 16L × 3 ethyl acetate, and organic facies abandons.Aqueous phase
Sodium hydrate aqueous solution with 30% regulates pH to 9～11, stirs 10min, sucking filtration.10 liters of dehydrated alcohol room temperature making beating of filter cake
30min, sucking filtration.It is heated to return stirring 30min with 40 liters of dehydrated alcohol again, is cooled to 25～35 DEG C.Sucking filtration, filter cake 45～65
DEG C vacuum drying, obtain white powder 3640g, yield 75%.
The synthesis of 2.C8 compound
The double-layer glass reaction kettle of 100L adds intermediate C7 3564g(1eq), CDI 2268g(1.8eq) and 18.9L tetrahydrochysene
Furan, keeps outer temperature 20～25 DEG C, is added thereto to DBU 2128g(1.8eq), control temperature when adding DBU less than 30 DEG C.
Stirring 90min.TLC monitoring is after reaction completes, drip in reactor sodium sulfite solution (4.14 kilograms of sodium sulfitees and
32.4 liters of water) and 36 liters of ethyl acetate stir 30 minutes after stand 15 minutes.21.6 liters of saturated aqueous common salts are added after removing water layer
Extraction, after removing water layer, organic layer 40～45 DEG C of evaporated under reduced pressure, obtain yellow solid, add 9 liters of dehydrated alcohol, temperature rising reflux
Being cooled to room temperature sucking filtration after 30 minutes, the solid that sucking filtration obtains is cooled to room after adding 10.8 liters of dehydrated alcohol backflows 30 minutes
Temperature, sucking filtration gained solid, 35～45 DEG C are vacuum dried to obtain C8 3388g, yield 90%.
3. the synthesis of Azilsartan crude product
(sodium hydroxide of 2.78Kg is configured to 27.8Kg's to add sodium hydrate aqueous solution in the double-layer glass reaction kettle of 100L
10% aqueous solution), 3363g intermediate C8, heat up stirring, and temperature is maintained at 50～70 DEG C, stirs 1.5 hours.TLC monitors reaction
It is basically completed, in reaction system, adds 19L water, be cooled to room temperature, be slowly added dropwise the hydrochloric acid solution of 10% to pH=3.5～4.5
(PH meter), (if there being sodium salt large area to separate out when acid adjustment starts, the ethanol that can add 2 times of C8 volumes makes it dissolve).Add
28.5L acetone stirs 15 minutes, sucking filtration.Filter cake 6.7L ethanol rinse, 35～45 DEG C of vacuum dryings obtain Azilsartan crude product
3059g, yield 96.8%.
4. Azilsartan is refined
Azilsartan crude product 3000g adds in 84L ethanol, is heated to 75～78 DEG C, molten clear after heat filtering immediately, filtrate is the coldest
But to 5～10 DEG C, stir 1 hour, filter, filter cake 3L dehydrated alcohol drip washing, filter cake 35～45 DEG C of vacuum drying, obtain solid
2700 grams, yield 90%.HPLC detects purity 99.903%.HPLC spectrogram is shown in Fig. 1.
1H-NMR (400MHz, DMSO-d6), δ: 1.45 (3H, t), 4.59 (2H, q), 5.73 (2H, s), 6.97-7.77
(11H, m), 12.51 (1H, s), 13.37 (1H, s).
Embodiment 2
The synthesis of 1.C7 compound
100L double-layer glass reaction kettle adds oxammonium hydrochloride. 14.6 kilograms (10eq) and 10.6 liters of water, stirs 10min, add three
21.2 kilograms of ethamine (10eq), stirs 10min.Add initiation material C6 9 kilograms (1eq), 53 liter of 95% ethanol, stir evenly.Feed intake
After completing, starting to warm up to backflow, reflux 10h.TLC follows the tracks of reaction process, after raw material fundamental reaction completes, stops heating,
It is naturally cooling to 20～35 DEG C.Sucking filtration, filter cake is with 10 liters of washings.Being put into by filter cake in reactor, (5.2 liters dense to add dilute hydrochloric acid
Hydrochloric acid is made into 52 aqueous solution), pull an oar 90min.Sucking filtration, filtrate extracts by 32L × 3 ethyl acetate, and organic facies abandons.Aqueous phase is used
The sodium hydrate aqueous solution regulation pH to 9～11 of 30%, stirs 10min, sucking filtration.20 liters of dehydrated alcohol room temperature making beating of filter cake
30min, sucking filtration.It is heated to return stirring 30min with 80 liters of dehydrated alcohol again, is cooled to 25～35 DEG C.Sucking filtration, filter cake 45～65
DEG C vacuum drying, obtain white powder 6892g, yield 71%.
The synthesis of 2.C8 compound
The double-layer glass reaction kettle of 200L adds intermediate C7 6800g(1eq), CDI 4327g(1.8eq) and 36L tetrahydrochysene furan
Mutter, keep outer temperature 20～25 DEG C, be added thereto to DBU 4059g(1.8eq), control temperature when adding DBU less than 30 DEG C.Stir
Mix 90min.After TLC monitoring reaction completes, in reactor, drip sodium sulfite solution (7.9 kilograms of sodium sulfitees and 62
Rise water) and 68.7 liters of ethyl acetate stir 30 minutes after standing 15 minutes.42 liters of saturated aqueous common salt extractions are added after removing water layer,
After removing water layer, organic layer 40～45 DEG C of evaporated under reduced pressure, obtain yellow solid, add 17.2 liters of dehydrated alcohol, temperature rising reflux 30
Being cooled to room temperature sucking filtration after minute, the solid that sucking filtration obtains is cooled to room after adding 20.7 liters of dehydrated alcohol backflows 30 minutes
Temperature, sucking filtration gained solid, 35～45 DEG C are vacuum dried to obtain C8 6393g, yield 89%.
3. the synthesis of Azilsartan crude product
(sodium hydroxide of 5.21Kg is configured to 52.1Kg's to add sodium hydrate aqueous solution in the double-layer glass reaction kettle of 200L
10% aqueous solution), 6300g intermediate C8, heat up stirring, and temperature is maintained at 50～70 DEG C, stirs 1.5 hours.TLC monitors reaction
Be basically completed, in reaction system, add 35.6L water, be cooled to room temperature, be slowly added dropwise the hydrochloric acid solution of 10% to pH=3.5～
4.5(PH counts), (if there being sodium salt large area to separate out when acid adjustment starts, the ethanol that can add 2 times of C8 volumes makes it dissolve).Add
53.4L acetone stirs 15 minutes, sucking filtration.Filter cake 12.6L ethanol rinse, it is thick that 35～45 DEG C of vacuum dryings obtain Azilsartan
Product 5606g, yield 94.7%.
4. Azilsartan is refined
Azilsartan crude product 5600g adds in 156.8L ethanol, is heated to 75～78 DEG C, molten clear after heat filtering immediately, filtrate is delayed
Slow cool down, to 5～10 DEG C, stirs 1 hour, filters, filter cake 5.6L dehydrated alcohol drip washing, filter cake 35～45 DEG C of vacuum drying,
To solid 5006 grams, yield 89.4%.HPLC detects purity 99.952%.HPLC spectrogram is shown in Fig. 2.
1H-NMR (400MHz, DMSO-d6), δ: 1.49 (3H, t), 4.62 (2H, q), 5.69 (2H, s), 7.07-7.87
(11H, m), 12.47 (1H, s), 13.23 (1H, s).
Being found by contrast, compared with the prior art, the scale of the present invention is obviously improved, and product purity also reaches
More than 99.9%, meet the industrialization production requirements of crude drug.
Claims (10)
1. a preparation method for Azilsartan, the method comprises the steps:
1) initiation material C6 is in second alcohol and water, under the effect of alkali, after oxammonium hydrochloride. additive reaction, is cooled to room temperature and takes out
Filter, after filter cake washing, pulls an oar with dilute hydrochloric acid, and the filtrate that sucking filtration obtains is extracted with ethyl acetate, and sodium hydroxide solution is used in water intaking mutually
Adjust pH to 9～11, after the filter cake dehydrated alcohol backflow making beating that sucking filtration obtains, 45～65 DEG C of vacuum drying after sucking filtration is the most dry,
To Azilsartan oxime；
2) the Azilsartan oxime prepared in step 1) and N, N '-carbonyl dimidazoles (CDI) cyclization in the basic conditions, reaction prepares
Azilsartan ethyl ester, uses NaHSO3Aqueous solution cancellation is reacted, ethyl acetate extractive reaction liquid, more organic with saturated aqueous common salt washing
Phase, evaporated under reduced pressure solvent, pull an oar with alcohol reflux, sucking filtration gained solid 35～45 DEG C of vacuum drying；
3) step 2) in the Azilsartan ethyl ester for preparing be hydrolyzed in sodium hydrate aqueous solution reaction, regulate pH with dilute hydrochloric acid
To 3.5～4.5, adding sucking filtration after acetone stirring, after filter cake alcohol flushing, it is thick that 35～45 DEG C of vacuum drying obtain Azilsartan
Product；
4) the refined crystalline substance that turns of the Azilsartan crude product dehydrated alcohol prepared in step 3) i.e. obtains Azilsartan, and 35～45 DEG C of vacuum are done
Dry.
The preparation method of Azilsartan the most according to claim 1, it is characterised in that the initiation material described in step 1)
C6 is 2-ethyoxyl-1-{ [((2 '-hydroxyl ammonia auxotox radical) double phenyl)-4-base]-methyl }-1H-benzimidazole--7-carboxylic acid
Ethyl ester, alkali is triethylamine, and the additive reaction temperature of initiation material C6 and oxammonium hydrochloride. is 82～90 DEG C, the response time be 8～
10h, the mol ratio of initiation material C6, oxammonium hydrochloride. and triethylamine is 1: 5～10: 5～10, the quality of sodium hydroxide solution
Concentration is 10～50%.
The preparation method of Azilsartan the most according to claim 1, it is characterised in that the initiation material described in step 1)
C6 is 10h with the additive reaction time of oxammonium hydrochloride., and the mol ratio of initiation material C6, oxammonium hydrochloride. and triethylamine is 1: 10:
10, the mass concentration of sodium hydroxide solution is 30%.
The preparation method of Azilsartan the most according to claim 1, it is characterised in that step 1) and step 2) described in
Dehydrated alcohol beating time 20min～40min.
The preparation method of Azilsartan the most according to claim 1, it is characterised in that step 1) and step 2) described in
Dehydrated alcohol beating time is 30min.
The preparation method of Azilsartan the most according to claim 1, it is characterised in that step 2) described in alkali be 1,8-
Diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), Azilsartan oxime, the mol ratio of CDI and DBU be: 1: 1.2～1.8
: 1.2～1.8, ring-closure reaction temperature is 20～30 DEG C, and the response time is 1～2h, and vacuum distillation temperature is 40～45 DEG C.
The preparation method of Azilsartan the most according to claim 1, it is characterised in that step 2) described in Azilsartan
Oxime, the mol ratio of CDI and DBU are 1: 1.8: 1.8, and ring-closure reaction temperature is 25 DEG C, and the response time is 90min.
The preparation method of Azilsartan the most according to claim 1, it is characterised in that the sodium hydroxide described in step 3)
The mass concentration of aqueous solution is 5～10%；The mol ratio of Azilsartan ethyl ester and sodium hydroxide is 1: 3～10, and hydrolysis temperature is
50～70 DEG C, the response time is 1～2h, and the mass concentration of dilute hydrochloric acid is 10%, and regulation pH is 2.5～4.5.
The preparation method of Azilsartan the most according to claim 1, it is characterised in that the sodium hydroxide described in step 3)
The mass concentration of aqueous solution is 10%；The mol ratio of Azilsartan ethyl ester and sodium hydroxide is 1: 10, and hydrolysis temperature is 70 DEG C,
Response time is 90min, and dilute hydrochloric acid regulation pH is 3.3.
The preparation method of Azilsartan the most according to claim 1, it is characterised in that the recrystallization described in step 4)
Temperature is 75～78 DEG C.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279140A (en) * | 2016-08-12 | 2017-01-04 | 合肥久诺医药科技有限公司 | A kind of preparation method of Azilsartan contamination levels product |
| CN106749216A (en) * | 2016-12-30 | 2017-05-31 | 湖南千金湘江药业股份有限公司 | A kind of process for purification of crystal formation A Azilsartans |
| JP2018002672A (en) * | 2016-07-05 | 2018-01-11 | 株式会社トクヤマ | Manufacturing method of amidoxime compound which become intermediate of azilsartan, and manufacturing method of azilsartan |
| WO2018008219A1 (en) * | 2016-07-05 | 2018-01-11 | 株式会社トクヤマ | Azilsartan intermediate, azilsartan, method for producing azilsartan intermediate, and method for producing azilsartan |
| JP2018008889A (en) * | 2016-07-13 | 2018-01-18 | 株式会社トクヤマ | Method for producing azilsartan alkyl ester, and method for producing azilsartan |
| JP2018076258A (en) * | 2016-11-09 | 2018-05-17 | 株式会社トクヤマ | Azilsartan alkyl ester, method for producing azilsartan methyl ester, and method for producing azilsartan |
| CN108658961A (en) * | 2018-06-13 | 2018-10-16 | 北京新领先医药科技发展有限公司 | A kind of preparation method of Azilsartan |
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| CN103664921A (en) * | 2013-11-27 | 2014-03-26 | 湖南千金湘江药业股份有限公司 | Azilsartan of crystal form A, and preparation method thereof |
| CN104418807A (en) * | 2013-09-09 | 2015-03-18 | 天津药物研究院 | Preparation method of 2-ethoxyl-1-[[2'-(hydroxyl amidino)-biphenylyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid and ester derivatives thereof |
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Cited By (8)
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|---|---|---|---|---|
| JP2018002672A (en) * | 2016-07-05 | 2018-01-11 | 株式会社トクヤマ | Manufacturing method of amidoxime compound which become intermediate of azilsartan, and manufacturing method of azilsartan |
| WO2018008219A1 (en) * | 2016-07-05 | 2018-01-11 | 株式会社トクヤマ | Azilsartan intermediate, azilsartan, method for producing azilsartan intermediate, and method for producing azilsartan |
| JP2018008889A (en) * | 2016-07-13 | 2018-01-18 | 株式会社トクヤマ | Method for producing azilsartan alkyl ester, and method for producing azilsartan |
| CN106279140A (en) * | 2016-08-12 | 2017-01-04 | 合肥久诺医药科技有限公司 | A kind of preparation method of Azilsartan contamination levels product |
| JP2018076258A (en) * | 2016-11-09 | 2018-05-17 | 株式会社トクヤマ | Azilsartan alkyl ester, method for producing azilsartan methyl ester, and method for producing azilsartan |
| CN106749216A (en) * | 2016-12-30 | 2017-05-31 | 湖南千金湘江药业股份有限公司 | A kind of process for purification of crystal formation A Azilsartans |
| CN106749216B (en) * | 2016-12-30 | 2021-05-04 | 湖南千金湘江药业股份有限公司 | Refining method of crystal form A azilsartan |
| CN108658961A (en) * | 2018-06-13 | 2018-10-16 | 北京新领先医药科技发展有限公司 | A kind of preparation method of Azilsartan |
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