CN106749216A - A kind of process for purification of crystal formation A Azilsartans - Google Patents
A kind of process for purification of crystal formation A Azilsartans Download PDFInfo
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- CN106749216A CN106749216A CN201611258343.3A CN201611258343A CN106749216A CN 106749216 A CN106749216 A CN 106749216A CN 201611258343 A CN201611258343 A CN 201611258343A CN 106749216 A CN106749216 A CN 106749216A
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- crystal formation
- azilsartan
- azilsartans
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The present invention relates to field of medicaments, a kind of process for purification of crystal formation A Azilsartans is disclosed.Comprise the following steps：S1 mixes ethyl acetate and absolute ethyl alcohol, and Azilsartan crude product is added after heating, stir it is molten it is clear after carry out press filtration；, by the filtrate in S1 in 20 ~ 25 DEG C of stirred crystallizations of temperature, after filtering, filter residue is through 24 mesh sieve whole grains for S2；Raw material is dried by the way of fluidized drying and gradient increased temperature；50 ~ 70min is dried under normal temperature condition, then is heated up 50 ~ 70min, Task-size Controlling D (90) is dried at 40 ± 2 DEG C：300~400μm；Then heat to 50 ± 2 DEG C of 2 ~ 3h of drying, Task-size Controlling D (90)：100 ~ 200 μm, Azilsartan finished product is obtained after cooling.Present invention substantially reduces it is refined when required organic solvent consumption, simultaneously, the drying of raw material is carried out using fluidized drying and gradient increased temperature mode, the crystal formation A Azilsartans stablized, obtain up to more than 90% refined yield, up to more than 99.7%, dissolvent residual (ethanol) is less than 0.3% to purity, and drying time also foreshortens to 3 ~ 6h.
Description
Technical field
The present invention relates to field of medicaments, more particularly to a kind of process for purification of crystal formation A Azilsartans.
Background technology
Azilsartan (English name Azilsartan) is that a kind of blood vessel of the treatment vascular hypertension being in research and development is tight
Element II receptor antagonist pharmaceuticals are opened, is hindered by the combination of selective exclusion Angiotensin II and vascular smooth muscle AT1 acceptors
The vasoconstriction effect of disconnected Angiotensin II, is used for treating vascular hypertension, is also the currently the only blood in late-stage clinical
Angiotensin II receptor antagonists (husky smooth class) medicine.
The patent report of crystal formation A Azilsartans has CN1040755C, EP0520423, US5243054, CN102766139A,
A of CN92105152C, CN 103930419 etc..Wherein, Chinese patent CN92105152C (Priority Patent JP1991157194)
Embodiment 1 disclose the preparation method of Azilsartan.The saponification in methyl alcohol/LiOH of Azilsartan methyl esters, obtains after acid treatment
Azilsartan crude product, then recrystallizes in ethyl acetate, obtains colourless rhomboidan, and gained compound is solvate, is contained
0.5 molecule ethyl acetate and 0.2 molecular water, fusing point are 156-157 DEG C.This refined mode has the disadvantage A Qisha after soda acid treatment
Smooth meeting decomposed, produces other degradation impurities.In patent CN1040755C specifications, page 60 discloses a kind of Azilsartan
Preparation method, be directed to the separation method of its crystal formation, will wash with water organic after product distributed in the water and chloroform
Layer, uses re-crystallizing in ethyl acetate again after solvent evaporated.Vacuum drying 12h (45 DEG C~50 DEG C, vacuum≤- 0.08Mpa)
WO2012107814A1 discloses the preparation method of Azilsartan, but it is crystal type or solvation also not illustrate
Thing.It is (hereinafter referred to as brilliant that Chinese patent CN102827153A discloses the crystal formation that the method recrystallized with absolute ethyl alcohol obtains
Type A), the characteristic peak of PXRD is expressed as 9.01 °, 12.60 °, 18.21 ° with 2 θ (± 0.2 °)；Preferably 9.01 °, 12.60 °,
18.21°、19.21°、21.37°、24.42°、25.25°、26.58°.Chinese patent CN102766139A also discloses that various heavy
Method for crystallising prepares the crystal formation of Azilsartan, compares PXRD collection of illustrative plates and other data, and that obtain is crystal formation A.This refined side
The shortcoming of formula is to be 20 times of volumes of its crude product using absolute ethyl alcohol quantity of solvent needed for refined, and needs to be heated to the shape that flows back
State, finished product is dried needs more than 12h, commercially produces high cost.
The document J.Med.Chem.1996,39,5228-5235 and 881-883 of Chinese Journal of Pharmaceuticals 2010,41 (12)
Be reported in final step to Azilsartan can be recrystallized to give the Azilsartan of white solid with absolute ethyl alcohol, and fusing point is
190 DEG C~191 DEG C.
The problem that process above is primarily present has：1st, refining solvent system is chaotic or purifying process is complicated, causes A Qisha
Smooth raw material crystal formation is complicated.Because Azilsartan raw material has unformed and polymorphism, different dicyandiamide solutions can be obtained
The Azilsartan of different crystal forms；2nd, drying time is more long, aftertreatment technology poor reproducibility.Azilsartan is easy to point at high temperature
Solution.Drying temperature is relatively low, and drying time is very long.3rd, drying temperature control is not strong, Azilsartan is formed solvate, or
Azilsartan is excessively thick or meticulous due to particle, particle internal moisture or solvent is dried completely, causes relevant material to increase,
Organic solvent residual.4th, refining solvent amount is big, obtains the organic solvent mass ratio that crystal formation A uses and is about 20~25 times, is unfavorable for
The cost control commercially produced.
The content of the invention
It is an object of the invention to solve prior art problem, there is provided a kind of process for purification of crystal formation A Azilsartans, we
The yield and purity of method are higher, greatly reduce the consumption of refined required organic solvent, reduce production cost, and product crystal formation is steady
Fixed, process is simple, the time is short, significantly reduces the content about material and dissolvent residual, it is ensured that the peace in clinical practice
Full property and validity.
The object of the invention is achieved through the following technical solutions：
A kind of process for purification of crystal formation A Azilsartans, comprises the following steps：
S1. it is 1 by mass ratio:2~4 ethyl acetate and absolute ethyl alcohol mixing, A Qi is added after being heated to 50~60 DEG C
Husky smooth crude product, stir it is molten it is clear after carry out press filtration；
S2. by the filtrate in S1 in 20~25 DEG C of stirred crystallizations of temperature, filter, filter residue is through 24 mesh sieve whole grains；Using boiling
Dry and the mode of gradient increased temperature is dried to raw material；50~70min is dried under normal temperature condition, then is heated up at 40 ± 2 DEG C
Dry 50~70min, Task-size Controlling D (90)：300~400 μm；Then heat to 50 ± 2 DEG C of 2~3h of drying, Task-size Controlling D
(90)：100~200 μm, Azilsartan finished product is obtained after cooling.
Preferably, the quality sum of ethyl acetate described in S1 and absolute ethyl alcohol is 3~3.5 times of Azilsartan crude product.
Preferably, the mass values of ethyl acetate described in S1 and absolute ethyl alcohol are 1:3.
Preferably, 2800~3000m of fluidized drying intake in S23/h。
Preferably, dry 60min in S2 under normal temperature condition, then to heat up and dry 60min, Task-size Controlling D (90) at 40 DEG C：
300~400 μm；Then heat to 50 DEG C and dry 2h, Task-size Controlling D (90)：100~200 μm.
Compared with prior art, the present invention has the advantages that：
The present invention selects the 1 of mass ratio:Used as solvent, solvent volume is only crude product to 2~4 ethyl acetate and absolute ethyl alcohol
3~3.5 times, the consumption of required organic solvent when greatly reducing refined, reduce production cost.A Qi is dissolved at 50~60 DEG C
Husky smooth crude product, reduces refined solution temperature, it is to avoid long-time temperature is too high to produce decomposition to Azilsartan.
The drying of raw material is carried out using fluidized drying and gradient increased temperature mode, the crystal formation A Azilsartans stablized are obtained
Up to more than 90% refined yield, up to more than 99.7%, dissolvent residual (ethanol) is less than 0.3% to purity, and when drying
Between by originally foreshortening to 3~6h more than 12h.
Product stable crystal form obtained in this hair, process is simple is adapted to the big production of commercialization.
Brief description of the drawings
Fig. 1 is the crystal formation detection figure of the gained Azilsartan finished product of embodiment 3；
Fig. 2 is the relevant material pattern of the gained Azilsartan finished product of embodiment 3；
Fig. 3 is the dissolvent residual collection of illustrative plates of the gained Azilsartan finished product of embodiment 3.
Wherein, the peak area 4.8 in Fig. 2 during retention time 4.557min, peak height 0.3；During retention time 5.154min
Peak area 9.9, peak height 0.9；Peak area 13.7 during retention time 9.470min, peak height 1.3；During retention time 14.572min
Peak area 2.5, peak height 0.2；Peak area during retention time 16.446min is 21069.2, and peak height is 2787.2；During reservation
Between 16.985min when peak area 2.6, peak height 0.2；Peak area 2.3 during retention time 20.726min, peak height 0.3；Retain
Peak area 9.0 during time 24.221min, peak height 1.0；Peak area 4.1 during retention time 31.357min, peak height 0.3.
Peak area 54.8 in Fig. 3 during retention time 6.188min, peak height 14.4；Peak during retention time 16.564min
Area is 68580.5, peak height 6881.4.
Specific embodiment
The present invention can be explained further and illustrate with reference to specific examples below, but specific embodiment is not to the present invention
There is any type of restriction.If not specializing, technological means used is well known to those skilled in the art in embodiment
Conventional meanses, it is raw materials used to be commercial goods.
Embodiment 1
Interior input 1kg ethyl acetate and 3kg absolute ethyl alcohols mix in glass reaction kettle, and heating-up temperature is to 50~55 DEG C
Afterwards, Azilsartan crude product 1.3kg is put into, control temperature is in 50~55 DEG C of stirrings to solution clarification.
20~25 DEG C are cooled to rapidly, and maintain this temperature stirred crystallization.Suction filtration, filter residue is sieved by oscillating granulator
Whole grain, screen cloth is 24 mesh, is then put into boiling drier, closes dog-house.The intake 2800 of setting boiling drier~
3000m338 DEG C of gradient increased temperature dries 70min, Task-size Controlling D (90) after 50min is dried under/h, normal temperature：300~400 μm, 50 DEG C
Dry 2~3h, Task-size Controlling D (90)：100~200 μm, material is cooled to 20 ± 5 DEG C, obtains Azilsartan finished product 1.25kg, receives
Rate 96%, crystal formation is A crystal formations, purity 99.81%, dissolvent residual (ethanol) 0.16%.
Embodiment 2
10kg ethyl acetate and the mixing of 40kg absolute ethyl alcohols are put into treatment tank, heating-up temperature is to 50~55 DEG C.Input
Azilsartan crude product 14.29kg, control temperature is in 50~55 DEG C of stirrings to solution clarification.
Press filtration after press filtration is finished, is cooled to rapidly 20~25 DEG C, and maintain this temperature stirred crystallization to crystallizing tank.Filtering,
By oscillating granulator sieving whole grain, screen cloth is 24 mesh to filter residue, in input boiling drier, closes dog-house.Air intake is set
2800~3000m of amount342 DEG C of gradient increased temperature dries 50min, Task-size Controlling D (90) after 60min is dried under/h, normal temperature：300~
400 μm, 50 DEG C of 2~3h of drying, Task-size Controlling D (90)：100~200 μm, material is cooled to 20 ± 5 DEG C, obtains Azilsartan finished product
13.29kg, yield 93%, crystal formation is A crystal formations, purity 99.82%, dissolvent residual (ethanol) 0.20%.
Embodiment 3
100kg ethyl acetate and the mixing of 200kg absolute ethyl alcohols are put into treatment tank, heating-up temperature is to 50~55 DEG C.Throw
Enter Azilsartan crude product 90.9kg, control temperature is in 50~55 DEG C of stirrings to solution clarification.
Press filtration after press filtration is finished, is cooled to rapidly 20~25 DEG C, and maintain this temperature stirred crystallization to crystallizing tank.Filtering,
By oscillating granulator sieving whole grain, screen cloth is 24 mesh to filter residue, in input boiling drier, closes dog-house.Air intake is set
2800~3000m of amount340 DEG C of gradient increased temperature dries 60min, Task-size Controlling D (90) after 60min is dried under/h, normal temperature：300~
400 μm, 50 DEG C of 2~3h of drying, Task-size Controlling D (90)：100~200 μm, material is cooled to 20 ± 5 DEG C, obtains Azilsartan finished product
85.45kg, yield 94%, crystal formation is A crystal formations, purity 99.77% (i.e. relevant content of material), dissolvent residual (ethanol)
0.08%.
The crystal formation testing result of gained Azilsartan finished product is shown in Fig. 1~Fig. 3.Specifying information is shown in Table 1 in Fig. 1.
Table 1
Comparative example 1
The interior input 18kg absolute ethyl alcohols in glass reaction kettle, heating-up temperature is to 50~55 DEG C.Input Azilsartan crude product
1.0kg, control temperature is in 50~55 DEG C of stirrings to solution clarification.
20~25 DEG C are cooled to rapidly, and maintain this temperature stirred crystallization.Suction filtration, vacuum decompression dry (45~50 DEG C,
12h), Azilsartan finished product 0.67kg, yield 67% are obtained, crystal formation is A crystal formations, purity 99.74%, dissolvent residual (ethanol)
0.6%.
Comparative example 2
The interior input 2kg ethyl acetate in glass reaction kettle, heating-up temperature is to 50~55 DEG C.Input Azilsartan crude product
1.0kg, control temperature is in 45~50 DEG C of stirrings to solution clarification.It is rapid to be cooled to 20~25 DEG C, and maintain this temperature to stir knot
It is brilliant.Suction filtration, vacuum decompression dry (45~50 DEG C, 8h), obtain Azilsartan finished product 0.34kg, yield 34%, and crystal formation is A crystal formations>
90%, purity 99.65%, dissolvent residual (ethyl acetate) 0.62%.
Comparative example 3
Interior input 1kg ethyl acetate and 3kg absolute ethyl alcohols in glass reaction kettle, heating-up temperature is to 50~55 DEG C.Input
Azilsartan crude product 1.3kg, control temperature is in 50~55 DEG C of stirrings to solution clarification.20~25 DEG C are cooled to rapidly, and are maintained
This temperature stirred crystallization.Suction filtration, vacuum drying 4h, obtain Azilsartan finished product 1.25kg, yield 96%, and crystal formation is A crystal formations, purity
99.82%, dissolvent residual (ethanol) 1.07%.Continue to be vacuum dried 8h, obtain Azilsartan finished product 1.25kg, yield 96% is brilliant
Type is A crystal formations, purity 99.82%, dissolvent residual (ethanol) 0.48%.
Claims (5)
1. a kind of process for purification of crystal formation A Azilsartans, it is characterised in that comprise the following steps：
S1. it is 1 by mass ratio:2 ~ 4 ethyl acetate and absolute ethyl alcohol mixing, adds Azilsartan thick after being heated to 50 ~ 60 DEG C
Product, stir it is molten it is clear after carry out press filtration；
S2. by the filtrate in S1 in 20 ~ 25 DEG C of stirred crystallizations of temperature, filter, filter residue is through 24 mesh sieve whole grains；Using fluidized drying
Mode with gradient increased temperature is dried to raw material；50 ~ 70min is dried under normal temperature condition, then is heated up 50 is dried at 40 ± 2 DEG C
~ 70min, Task-size Controlling D (90)：300~400μm；Then heat to 50 ± 2 DEG C of 2 ~ 3h of drying, Task-size Controlling D (90)：100~
200 μm, Azilsartan finished product is obtained after cooling.
2. the process for purification of crystal formation A Azilsartans according to claim 1, it is characterised in that ethyl acetate described in S1 and
The quality sum of absolute ethyl alcohol is 3 ~ 3.5 times of Azilsartan crude product.
3. the process for purification of crystal formation A Azilsartans according to claim 1, it is characterised in that ethyl acetate described in S1 and
The mass ratio of absolute ethyl alcohol is 1:3.
4. the process for purification of crystal formation A Azilsartans according to claim 1, it is characterised in that fluidized drying intake in S2
2800~3000m³/h。
5. the process for purification of crystal formation A Azilsartans according to claim 1, it is characterised in that in S2, done under normal temperature condition
Dry 60min, then to heat up and dry 60min, Task-size Controlling D (90) at 40 DEG C：300~400μm；50 DEG C of 2 ~ 3h of drying are then heated to,
Task-size Controlling D (90)：100~200μm.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108912109A (en) * | 2018-08-17 | 2018-11-30 | 珠海润都制药股份有限公司 | A kind of high-purity, small particle and azilsartan crude drug of low solvent residue and preparation method thereof |
| WO2019155922A1 (en) * | 2018-02-09 | 2019-08-15 | 株式会社トクヤマ | Method for producing azilsartan a-form crystal |
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| CN102766139A (en) * | 2012-08-14 | 2012-11-07 | 江苏先声药物研究有限公司 | Azilsartan polymorphic substance and preparation method thereof |
| CN103113364A (en) * | 2012-08-27 | 2013-05-22 | 南京华威医药科技开发有限公司 | Preparation method of azilsartan polymorphism |
| CN103435604A (en) * | 2013-08-28 | 2013-12-11 | 合肥久诺医药科技有限公司 | Refining method of high-purity azilsartan |
| CN103930419A (en) * | 2011-09-30 | 2014-07-16 | 广东东阳光药业有限公司 | Crystalline forms of azilsartan and preparation and uses thereof |
| CN104557899A (en) * | 2014-11-17 | 2015-04-29 | 江苏中邦制药有限公司 | Preparation method of azilsartan I-form crystal |
| CN105712984A (en) * | 2016-03-04 | 2016-06-29 | 江苏正大清江制药有限公司 | Preparation method of Azilsartan |
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| CN103930419A (en) * | 2011-09-30 | 2014-07-16 | 广东东阳光药业有限公司 | Crystalline forms of azilsartan and preparation and uses thereof |
| CN102766139A (en) * | 2012-08-14 | 2012-11-07 | 江苏先声药物研究有限公司 | Azilsartan polymorphic substance and preparation method thereof |
| CN103113364A (en) * | 2012-08-27 | 2013-05-22 | 南京华威医药科技开发有限公司 | Preparation method of azilsartan polymorphism |
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| CN104557899A (en) * | 2014-11-17 | 2015-04-29 | 江苏中邦制药有限公司 | Preparation method of azilsartan I-form crystal |
| CN105712984A (en) * | 2016-03-04 | 2016-06-29 | 江苏正大清江制药有限公司 | Preparation method of Azilsartan |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019155922A1 (en) * | 2018-02-09 | 2019-08-15 | 株式会社トクヤマ | Method for producing azilsartan a-form crystal |
| CN111699183A (en) * | 2018-02-09 | 2020-09-22 | 株式会社德山 | Method for producing azilsartan A-type crystal |
| JPWO2019155922A1 (en) * | 2018-02-09 | 2021-02-04 | 株式会社トクヤマ | Method for producing azilsartan type A crystal |
| JP7177796B2 (en) | 2018-02-09 | 2022-11-24 | 株式会社トクヤマ | Method for producing azilsartan type A crystal |
| CN108912109A (en) * | 2018-08-17 | 2018-11-30 | 珠海润都制药股份有限公司 | A kind of high-purity, small particle and azilsartan crude drug of low solvent residue and preparation method thereof |
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